28 results on '"Sofia Karkampouna"'
Search Results
2. Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity
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Federico La Manna, Marta De Menna, Nikhil Patel, Sofia Karkampouna, Maria De Filippo, Irena Klima, Peter Kloen, Lijkele Beimers, George N. Thalmann, Rob C. M. Pelger, Estela Jacinto, and Marianna Kruithof-de Julio
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bone metastasis ,PDX ,mTOR ,disulfiram ,prostate cancer ,ALDH ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Bone metastasis is the leading cause of prostate cancer (PCa) mortality, frequently marking the progression to castration-resistant PCa. Dysregulation of the androgen receptor pathway is a common feature of castration-resistant PCa, frequently appearing in association with mTOR pathway deregulations. Advanced PCa is also characterized by increased tumor heterogeneity and cancer stem cell (CSC) frequency. CSC-targeted therapy is currently being explored in advanced PCa, with the aim of reducing cancer clonal divergence and preventing disease progression. In this study, we compared the molecular pathways enriched in a set of bone metastasis from breast and prostate cancer from snap-frozen tissue. To further model PCa drug resistance mechanisms, we used two patient-derived xenografts (PDX) models of bone-metastatic PCa, BM18, and LAPC9. We developed in vitro organoids assay and ex vivo tumor slice drug assays to investigate the effects of mTOR- and CSC-targeting compounds. We found that both PDXs could be effectively targeted by treatment with the bivalent mTORC1/2 inhibitor Rapalink-1. Exposure of LAPC9 to Rapalink-1 but not to the CSC-targeting drug disulfiram blocked mTORC1/2 signaling, diminished expression of metabolic enzymes involved in glutamine and lipid metabolism and reduced the fraction of CD44+ and ALDEFluorhigh cells, in vitro. Mice treated with Rapalink-1 showed a significantly delayed tumor growth compared to control and cells recovered from the tumors of treated animals showed a marked decrease of CD44 expression. Taken together these results highlight the increased dependence of advanced PCa on the mTOR pathway, supporting the development of a targeted approach for advanced, bone metastatic PCa.
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- 2020
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3. Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures
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Sofia Karkampouna, Maria R. De Filippo, Charlotte K. Y. Ng, Irena Klima, Eugenio Zoni, Martin Spahn, Frank Stein, Per Haberkant, George N. Thalmann, and Marianna Kruithof-de Julio
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prostate cancer ,stroma signature ,patient-derived xenografts ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Resistance acquisition to androgen deprivation treatment and metastasis progression are a major clinical issue associated with prostate cancer (PCa). The role of stroma during disease progression is insufficiently defined. Using transcriptomic and proteomic analyses on differentially aggressive patient-derived xenografts (PDXs), we investigated whether PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern. RNA sequencing was performed on the PCa PDXs BM18 (castration-sensitive) and LAPC9 (castration-resistant), representing different disease stages. Using organism-specific reference databases, the human-specific transcriptome (tumor) was identified and separated from the mouse-specific transcriptome (stroma). To identify proteomic changes in the tumor (human) versus the stroma (mouse), we performed human/mouse cell separation and subjected protein lysates to quantitative Tandem Mass Tag labeling and mass spectrometry. Tenascin C (TNC) was among the most abundant stromal genes, modulated by androgen levels in vivo and highly expressed in castration-resistant LAPC9 PDX. The tissue microarray of primary PCa samples (n = 210) showed that TNC is a negative prognostic marker of the clinical progression to recurrence or metastasis. Stroma markers of osteoblastic PCa bone metastases seven-up signature were induced in the stroma by the host organism in metastatic xenografts, indicating conserved mechanisms of tumor cells to induce a stromal premetastatic signature. A 50-gene list stroma signature was identified based on androgen-dependent responses, which shows a linear association with the Gleason score, metastasis progression and progression-free survival. Our data show that metastatic PCa PDXs, which differ in androgen sensitivity, trigger differential stroma responses, which show the metastasis risk stratification and prognostic biomarker potential.
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- 2020
- Full Text
- View/download PDF
4. The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis
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Francesco Bonollo, George N. Thalmann, Marianna Kruithof-de Julio, and Sofia Karkampouna
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prostate cancer ,reactive stroma ,tumor microenvironment ,bone metastasis ,cancer associated fibroblasts ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.
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- 2020
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5. ALK1Fc Suppresses the Human Prostate Cancer Growth in in Vitro and in Vivo Preclinical Models
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Letizia Astrologo, Eugenio Zoni, Sofia Karkampouna, Peter C. Gray, Irena Klima, Joël Grosjean, Marie J. Goumans, Lukas J. A. C. Hawinkels, Gabri van der Pluijm, Martin Spahn, George N. Thalmann, Peter ten Dijke, and Marianna Kruithof-de Julio
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BMP9 ,ALK1 ,ALK2 ,ALK1Fc ,NOTCH ,prostate cancer ,Biology (General) ,QH301-705.5 - Abstract
Prostate cancer is the second most common cancer in men and lethality is normally associated with the consequences of metastasis rather than the primary tumor. Therefore, targeting the molecular pathways that underlie dissemination of primary tumor cells and the formation of metastases has a great clinical value. Bone morphogenetic proteins (BMPs) play a critical role in tumor progression and this study focuses on the role of BMP9- Activin receptor-Like Kinase 1 and 2 (ALK1 and ALK2) axis in prostate cancer. In order to study the effect of BMP9 in vitro and in vivo on cancer cells and tumor growth, we used a soluble chimeric protein consisting of the ALK1 extracellular domain (ECD) fused to human Fc (ALK1Fc) that prevents binding of BMP9 to its cell surface receptors and thereby blocks its ability to activate downstream signaling. ALK1Fc sequesters BMP9 and the closely related BMP10 while preserving the activation of ALK1 and ALK2 through other ligands. We show that ALK1Fc acts in vitro to decrease BMP9-mediated signaling and proliferation of prostate cancer cells with tumor initiating and metastatic potential. In line with these observations, we demonstrate that ALK1Fc also reduces tumor cell proliferation and tumor growth in vivo in an orthotopic transplantation model, as well as in the human patient derived xenograft BM18. Furthermore, we also provide evidence for crosstalk between BMP9 and NOTCH and find that ALK1Fc inhibits NOTCH signaling in human prostate cancer cells and blocks the induction of the NOTCH target Aldehyde dehydrogenase member ALDH1A1, which is a clinically relevant marker associated with poor survival and advanced-stage prostate cancer. Our study provides the first demonstration that ALK1Fc inhibits prostate cancer progression, identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. Altogether, these findings support the validity of ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.
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- 2017
- Full Text
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6. MP33-12 THE POTENTIAL ROLE OF CTLH COMPLEX IN THE PROSTATE CANCER
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Marta De Menna, Sofia Karkampouna, Eugenio Zoni, Marianna Kruithof-de Julio, and Mario Scarpa
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Oncology ,Prostate cancer ,medicine.medical_specialty ,business.industry ,Urology ,Internal medicine ,medicine ,medicine.disease ,Malignancy ,business - Abstract
INTRODUCTION AND OBJECTIVE:Prostate cancer (PCa) is the most frequent malignancy detected in men and the second leading cause of cancer-related male death in Europe. Current markers frequently fail...
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- 2021
7. PD44-09 STROMA TRANSCRIPTOMIC AND PROTEOMIC PROFILE OF PROSTATE CANCER METASTASIS XENOGRAFT MODELS REVEALS PROGNOSTIC VALUE OF STROMA SIGNATURES
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Irena Klima, G.N. Thalmann, Sofia Karkampouna, M.R. De Filippo, Eugenio Zoni, Frank Stein, M. Kruithof-De Julio, Per Haberkant, Charlotte K.Y. Ng, and Martin Spahn
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Transcriptome ,Prostate cancer ,Proteomic Profile ,Stroma ,business.industry ,Urology ,Cancer research ,medicine ,medicine.disease ,business ,Value (mathematics) ,Metastasis - Published
- 2021
8. Patient-derived xenografts and organoids model therapy response in prostate cancer
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Joel Grosjean, Peter Clark Gray, Jean-Philippe Theurillat, Sofia Karkampouna, Andrea Sboner, M. De Menna, M.R. De Filippo, George N. Thalmann, Andrea Garofoli, Eugenio Zoni, Andrej Benjak, Marco Bolis, Vera Genitsch, David Keller, Charlotte K.Y. Ng, Salvatore Piscuoglio, Irena Klima, Mark A. Rubin, Kenneth Eng, Arianna Vallerga, Tijmen H. Booij, Julio Marianna Kruithof-de, F. La Manna, Christian U. Stirnimann, and Mirjam Kiener
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Oncology ,medicine.medical_specialty ,Prostate cancer ,Therapy response ,business.industry ,Urology ,Internal medicine ,Organoid ,medicine ,medicine.disease ,business - Published
- 2021
9. The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis
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Marianna Kruithof-de Julio, Francesco Bonollo, Sofia Karkampouna, and George N. Thalmann
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0301 basic medicine ,Cancer Research ,Stromal cell ,cancer associated fibroblasts ,610 Medicine & health ,Review ,medicine.disease_cause ,lcsh:RC254-282 ,Metastasis ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Prostate ,medicine ,tumor microenvironment ,bone metastasis ,Tumor microenvironment ,business.industry ,Bone metastasis ,medicine.disease ,prostate cancer ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,reactive stroma ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Cancer-Associated Fibroblasts ,Carcinogenesis ,business - Abstract
Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.
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- 2020
10. Patient-derived xenografts and organoids model therapy response in prostate cancer
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Mirjam Kiener, Marianna Kruithof-de Julio, George N. Thalmann, Salvatore Piscuoglio, Marta De Menna, Maria R. De Filippo, Federico La Manna, Peter C. Gray, Andrea Sboner, Eugenio Zoni, Charlotte K.Y. Ng, Jo eumll Grosjean, David Keller, Christian U. Stirnimann, Sofia Karkampouna, Marco Bolis, Tijmen H. Booij, Martin Spahn, Irena Klima, Mark A. Rubin, Kenneth Eng, Andrea Garofoli, Jean-Philippe Theurillat, and Vera Genitsch
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Sorafenib ,Sunitinib ,Ponatinib ,Microsatellite instability ,SPOP ,Biology ,medicine.disease ,Primary tumor ,chemistry.chemical_compound ,Prostate cancer ,chemistry ,medicine ,Organoid ,Cancer research ,medicine.drug - Abstract
Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harboursBRCA2 and CHD1somatic mutations, shows anSPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelledin vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
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- 2020
11. Patient-derived xenografts and organoids model therapy response in prostate cancer
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Marco Bolis, Arianna Vallerga, Salvatore Piscuoglio, Andrej Benjak, Andrea Sboner, Federico La Manna, Mirjam Kiener, Joel Grosjean, Tijmen H. Booij, David Keller, Charlotte K.Y. Ng, Eugenio Zoni, Martin Spahn, Vera Genitsch, Sofia Karkampouna, Irena Klima, Mark A. Rubin, Kenneth Eng, Marianna Kruithof-de Julio, Christian U. Stirnimann, Jean-Philippe Theurillat, Andrea Garofoli, Maria R. De Filippo, Marta De Menna, George N. Thalmann, and Peter C. Gray
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0301 basic medicine ,Sorafenib ,Male ,Science ,Medizin ,General Physics and Astronomy ,610 Medicine & health ,Antineoplastic Agents ,SPOP ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cancer screening ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,medicine ,Organoid ,Humans ,Neoplasm Metastasis ,Cancer models ,Multidisciplinary ,Sunitinib ,business.industry ,Genome, Human ,Cancer stem cells ,Ponatinib ,Microsatellite instability ,Prostatic Neoplasms ,General Chemistry ,medicine.disease ,Primary tumor ,Xenograft Model Antitumor Assays ,3. Good health ,Organoids ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Androgens ,570 Life sciences ,biology ,business ,Transcriptome ,medicine.drug - Abstract
Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds., To date, patients still succumb to cancer, due to tumors not responding to therapy or ultimately acquiring resistance. Here the authors show that by exploiting patient derived organoids and a treatment-naïve patient derived xenograft, patient therapy can be personalized.
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- 2020
12. Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures
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Frank Stein, Maria R. De Filippo, Charlotte K.Y. Ng, Irena Klima, Per Haberkant, Martin Spahn, Eugenio Zoni, George N. Thalmann, Sofia Karkampouna, and Marianna Kruithof-de Julio
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0301 basic medicine ,stroma signature ,Cancer Research ,Stromal cell ,Urology ,610 Medicine & health ,lcsh:RC254-282 ,Article ,Metastasis ,Transcriptome ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Stroma ,medicine ,Proteomic Profile ,Tissue microarray ,biology ,Tenascin C ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,prostate cancer ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,patient-derived xenografts - Abstract
Simple Summary Currently, there is a need for prognostic tools that can stratify patients, who present with primary disease, based on whether they are at low or high risk for drug resistant and hormone-independent lethal metastatic prostate cancer. The aim of our study was to assess the potentially added value of tumor microenvironment (stroma) components for the characterisation of prostate cancer. By utilising patient derived-xenograft models we show that the molecular properties of the stroma cells are highly responsive to androgen hormone levels, and considerable ECM remodelling processes take place not only in androgen-dependent but also in androgen-independent tumor models. Transcriptomic mechanisms linked to osteotropism are conserved in bone metastatic xenografts, even when implanted in a different microenvironment. A stroma-specific gene list signature was identified, which highly correlates with Gleason score, metastasis progression and progression-free survival, and thus could potentially complement current patient stratification methods. Abstract Resistance acquisition to androgen deprivation treatment and metastasis progression are a major clinical issue associated with prostate cancer (PCa). The role of stroma during disease progression is insufficiently defined. Using transcriptomic and proteomic analyses on differentially aggressive patient-derived xenografts (PDXs), we investigated whether PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern. RNA sequencing was performed on the PCa PDXs BM18 (castration-sensitive) and LAPC9 (castration-resistant), representing different disease stages. Using organism-specific reference databases, the human-specific transcriptome (tumor) was identified and separated from the mouse-specific transcriptome (stroma). To identify proteomic changes in the tumor (human) versus the stroma (mouse), we performed human/mouse cell separation and subjected protein lysates to quantitative Tandem Mass Tag labeling and mass spectrometry. Tenascin C (TNC) was among the most abundant stromal genes, modulated by androgen levels in vivo and highly expressed in castration-resistant LAPC9 PDX. The tissue microarray of primary PCa samples (n = 210) showed that TNC is a negative prognostic marker of the clinical progression to recurrence or metastasis. Stroma markers of osteoblastic PCa bone metastases seven-up signature were induced in the stroma by the host organism in metastatic xenografts, indicating conserved mechanisms of tumor cells to induce a stromal premetastatic signature. A 50-gene list stroma signature was identified based on androgen-dependent responses, which shows a linear association with the Gleason score, metastasis progression and progression-free survival. Our data show that metastatic PCa PDXs, which differ in androgen sensitivity, trigger differential stroma responses, which show the metastasis risk stratification and prognostic biomarker potential.
- Published
- 2020
- Full Text
- View/download PDF
13. Synergic AR and dual-mTOR blockade delays advanced prostate cancer growth and alters tumor heterogeneity
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G.N. Thalmann, M. De Menna, F. La Manna, Sofia Karkampouna, and M. Kruithof-De Julio
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Prostate cancer ,business.industry ,Urology ,Cancer research ,Medicine ,DUAL (cognitive architecture) ,business ,medicine.disease ,Tumor heterogeneity ,PI3K/AKT/mTOR pathway ,Blockade - Published
- 2021
14. Personalised organoid drug treatment and therapy resistance characterization based on novel BRCA2 prostate cancer xenograft of SPOP-like phenotype and microsatellite instability
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Joel Grosjean, M.R. De Filippo, M. De Menna, Salvatore Piscuoglio, F. La Manna, G.N. Thalmann, M. Kruithof-De Julio, Tijmen H. Booij, Christian U. Stirnimann, Sofia Karkampouna, Eugenio Zoni, Charlotte K.Y. Ng, David Keller, Irena Klima, Andrea Sboner, Andrea Garofoli, Martin Spahn, Vera Genitsch, and A.R. Mark
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business.industry ,Urology ,Microsatellite instability ,SPOP ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:RC870-923 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,lcsh:RC254-282 ,Phenotype ,Drug treatment ,Prostate cancer ,Cancer research ,Organoid ,Medicine ,Treatment resistance ,business - Published
- 2020
15. Cripto blockade reduces prostate cancer reactivity to microenvironment and metastatic potential
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Peter Clark Gray, L. Staender, Sofia Karkampouna, Eugenio Zoni, F. La Manna, George N. Thalmann, and M. Kruithof-De Julio
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Prostate cancer ,business.industry ,Urology ,medicine ,Cancer research ,Reactivity (chemistry) ,medicine.disease ,business ,Cripto ,610 Medicine & health ,Blockade - Published
- 2019
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16. Abstract B18: Patient-derived xenograft and organoids models of prostate cancer
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Andrea Garofoli, Marianna Kruithof-de Julio, David Keller, Booij Tijmen, Jean-Philippe Theurillat, Marco Bolis, Christian U. Stirnimann, Charlotte K.Y. Ng, Irena Klima, Marta De Menna, Mirjam Kiener, Mark A. Rubin, George N. Thalmann, Martin Spahn, Vera Genitsch, Joel Grosjean, Maria R. De Filippo, Andrea Sboner, Sofia Karkampouna, Federico La Manna, Eugenio Zoni, and Salvatore Piscuoglio
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Cancer Research ,medicine.drug_class ,business.industry ,Microsatellite instability ,Cancer ,medicine.disease ,Androgen ,Primary tumor ,Drug repositioning ,Prostate cancer ,medicine.anatomical_structure ,Oncology ,medicine ,Cancer research ,Organoid ,Bone marrow ,business - Abstract
Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, mainly due to the lack of experimental models representing different disease stages. We aim to provide functional experimental and preclinical drug tools applicable for direct use with patient-derived material. Biopsies from metastatic PCa were used for the establishment of patient-derived xenografts (PDXs) by subcutaneous implantation. In vivo tumor growth kinetic in response to androgens was assessed by surgical castration and testosterone supplementation. RNA and whole-exome sequencing (WES) and organoid drug screens were used to characterize the genomic, transcriptomic, and functional properties. Organoid culture methodology was adapted in order to set up an automated medium-throughput organoid drug screen (Nexus Theragnostics automated platform) for screening standard-of-care compounds and candidates for drug repurposing. A novel case of PCa xenograft model derived from soft tissue metastasis (PNPCa) was established. RNAseq and WES confirmed transcriptomic and genomic similarity to the primary tumor. PNPCa harbors BRAC2 and CHD1 mutations and shows SPOP-like and FOXA1-like transcriptomic signature with microsatellite instability. PNPCa tumor growth is inhibited after androgen deprivation by castration, while androgen replacement leads to tumor reformation. No spontaneous tumor growth occurred after prolonged period of castration; however, scarce micrometastases were found in the bone marrow and lymph nodes. The treatment-naive and androgen-dependent properties of the PNPCa made it a candidate model for identification of potent drug compounds. PNPCa-derived organoid screens on standard-of-care and 74 FDA-approved compounds showed that mTOR pathway and multi-tyrosine kinase inhibitors, used for clinical treatment of other cancer types, have high impact on PCa organoid viability. Application of the organoid drug screen panel on two additional metastatic PDXs of advanced disease has allowed shortlisting of compounds for repurposing use in patient-derived organoid screens that can be routinely performed in a timeframe of few weeks, and thus, provide information on treatment decision. Treatment response of a treatment-naive, early metastatic PCa case (PNPCa PDX) highlights the potential of organoid screens to assess therapy response with extended applications for personalized screens. Citation Format: Sofia Karkampouna, Federico la Manna, Maria R. De Filippo, Mirjam Kiener, Marta De Menna, Eugenio Zoni, Joel Grosjean, Irena Klima, Andrea Garofoli, Marco Bolis, Jean-Philippe Theurillat, Vera Genitsch, David Keller, Booij Tijmen, Christian U. Stirnimann, Andrea Sboner, Charlotte K.Y. Ng, Salvatore Piscuoglio, Martin Spahn, Mark A. Rubin, George N. Thalmann, Marianna Kruithof-de Julio. Patient-derived xenograft and organoids models of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B18.
- Published
- 2020
17. MP81-16 MOLECULAR CHARACTERIZATION OF CANCER STEM CELLS FROM PROSTATE CANCER XENOGRAFTS
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Peter Clark Gray, Sofia Karkampouna, Marianna Kruithof-de Julio, George N. Thalmann, Joel Grosjean, Maria De Menna, and Markus Germann
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Prostate cancer ,Cancer stem cell ,business.industry ,Urology ,medicine ,Cancer research ,medicine.disease ,business - Published
- 2018
18. Emerging aspects of microRNA interaction with TMPRSS2-ERG and endocrine therapy
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Eugenio Zoni, Sofia Karkampouna, George N. Thalmann, Marianna Kruithof-de Julio, and Martin Spahn
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Male ,0301 basic medicine ,Oncogene Proteins, Fusion ,medicine.drug_class ,610 Medicine & health ,Biology ,Malignancy ,urologic and male genital diseases ,Biochemistry ,TMPRSS2 ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Endocrinology ,Transcriptional Regulator ERG ,microRNA ,medicine ,Humans ,Endocrine system ,Molecular Biology ,Serine Endopeptidases ,Prostatic Neoplasms ,Androgen ,medicine.disease ,Hormones ,3. Good health ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Hormone - Abstract
Prostate cancer (PCa) is the most common malignancy detected in males and the second most common cause of cancer death in western countries. The development of the prostate gland, is finely regulated by androgens which modulate also its growth and function. Importantly, androgens exert a major role in PCa formation and progression and one of the hypothesized mechanism proposed has been linked to the chromosomal rearrangement of the androgen regulated gene TMPRSS2 with ERG. Androgens have been therefore used as main target for therapies in the past. However, despite the development of endocrine therapies (e.g. androgen ablation), when PCa progress, tumors become resistant to this therapeutic castration and patients develop incurable metastases. A strategy to better understand how patients respond to therapy, in order to achieve a better patient stratification, consists in monitoring the levels of small noncoding RNAs (microRNAs). microRNAs are a class of small molecules that regulate protein abundance and their application as biomarkers to monitor disease progression has been intensely studied in the last years. In this review, we highlight the interactions between microRNAs and endocrine-related aspects of PCa in tissues. We focus on the modulation of TMPRSS2-ERG and Glucocorticoid Receptor (GR) by microRNAs and detail the influence of steroidal hormonal therapies on microRNAs expression.
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- 2018
19. MP41-10 MODELLING PROSTATE CANCER USING PRIMARY AND METASTATIC CANCEROIDS
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Antoinette Wetterwald, Lijkele Beimers, Eugenio Zoni, Martin Spahn, Marco G. Cecchini, Joel Grosjean, Federico La Manna, George N. Thalmann, Peter Kloen, Irena Klima, Sofia Karkampouna, and Marianna Kruithof-de Julio
- Subjects
Oncology ,CA15-3 ,medicine.medical_specialty ,Prostate cancer ,Primary (chemistry) ,business.industry ,Urology ,Internal medicine ,medicine ,medicine.disease ,business - Published
- 2017
20. CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer
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Peter Kloen, Sofia Karkampouna, Rob C.M. Pelger, G J L H van Leenders, Lijkele Beimers, Zoraide Granchi, E Snaar-Jagalska, F. La Manna, Lanpeng Chen, M D Henry, Eugenio Zoni, Esther I. Verhoef, Peter C. Gray, M. Kruithof-De Julio, G. van der Pluijm, Jonathan A. Kelber, Pathology, Other departments, APH - Personalized Medicine, APH - Quality of Care, Orthopedic Surgery and Sports Medicine, AMS - Restoration & Development, AMS - Ageing & Morbidty, and Other Research
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Mice, Nude ,Bone Neoplasms ,Kaplan-Meier Estimate ,Biology ,Cripto ,GPI-Linked Proteins ,Molecular oncology ,Metastasis ,03 medical and health sciences ,Prostate cancer ,Mice ,Growth factor receptor ,SDG 3 - Good Health and Well-being ,Cell Movement ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Cell Proliferation ,Cancer ,Bone metastasis ,Prostatic Neoplasms ,medicine.disease ,Neoplasm Proteins ,030104 developmental biology ,Gene Knockdown Techniques ,Immunology ,Cancer cell ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Original Article ,hormones, hormone substitutes, and hormone antagonists ,Neoplasm Transplantation - Abstract
CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDH(high) sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDH(low). Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDH(high) sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDH(high) sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.
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- 2017
21. Cripto/Grp78 drive the metastatic phenotype in human osteotropic prostate cancer
- Author
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Peter C. Gray, Rob C.M. Pelger, Lanpeng Chen, Julio Marianna Kruithof-de, Zoraide Granchi, Manna Federico La, Leenders Geert van, Eugenio Zoni, Ewa Snaar-Jagalska, Peter Kloen, der Pluijm Gabri van, Sofia Karkampouna, Ester Verhoef, and Lijkele Beimers
- Subjects
Oncology ,Prostate cancer ,medicine.medical_specialty ,business.industry ,Internal medicine ,Metastatic phenotype ,medicine ,General Medicine ,medicine.disease ,business ,Cripto - Published
- 2016
22. Abstract B060: Molecular characterization of cancer stem cells from patient-derived xenografts of advanced prostate cancer
- Author
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Sofia Karkampouna, Markus Germann, Marta De Menna, Peter C. Gray, Joel Grosjean, Marianna Kruithof-de Julio, and George N. Thalmann
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Cancer Research ,biology ,CD44 ,Cancer ,urologic and male genital diseases ,medicine.disease ,Stem cell marker ,Prostate cancer ,Oncology ,Cancer stem cell ,Cancer cell ,biology.protein ,medicine ,Cancer research ,Stem cell ,Progenitor cell - Abstract
Introduction: Androgen-deprivation therapy is the standard treatment for prostate cancer. Despite the initial response, a fraction of cases manifest progression to castration-resistant prostate cancer. The paradigm of PCa recurrence is the existence of androgen-independent cancer stem cells, which differentiate into androgen-dependent cancer cells that reinitiate tumor growth. The phenotypic properties of cancer stem cells versus highly proliferative progenitor cells/facultative stem cells remain to be further characterized in terms of androgen receptor signaling, quiescence/proliferation, tumorigenicity, and therapy resistance. Methods: To address the molecular basis of CSC switch from androgen-dependency to independency we have employed two patient-derived xenograft models (LAPC-9 and BM-18) that have different androgen sensitivity properties. We have performed microarray and proteomic analysis of BM-18 tumor tissues prior to and following castration as well as androgen replacement. To characterize the cancer stem cells in these models we have isolated different subpopulations based on combination of selected markers and assessed the transcriptomic changes, proteomic profile, and in vivo self-renewal. Results: Castration induces a rapid tumor volume decrease in the BM-18 and a stabilization of tumor burden in the LAPC-9, reflecting different androgen-dependent cell states. Proteomic analysis of bulk BM-18 tumors (intact, 14 days post castration, 50 days post androgen replacement) indicates an enrichment of stem cell markers upon castration; CD44, NKX3.1, and ALDH1 isoforms. Microarray analysis has confirmed upregulation of CD44 and ALDH1A1 at castrated state, and downregulation of expression upon androgen replacement at early time points (24 hours). We have isolated CD44+/-ALDHhigh/low subpopulation by flow cytometry and analyzed their transcriptome and proteomic changes. Castration in the BM-18 model induces an increase in the subpopulations of CD44+/ALDHlow (from 0.44% to 2.3%) and CD44+/ALDHhigh (from 0.06% to 0.38%). However, the same subpopulations are decreased in the LAPC-9 model upon castration, while only the CD44-/ALDHhigh subset is enriched (from 3.5% to 7.1%). Conclusions: Different androgen-independent cancer stem cell subpopulations may be distinguished by the ALDH activity status in combination with CD44. The androgen-independent cells in the BM-18 androgen-dependent model are reflected by enrichment of CD44 expression, as well as a rare double positive population. In the androgen-independent LAPC-9 model, CD44 expression is contrastingly decreased, potentially reflecting androgen-dependent CD44+ cells, and ALDH activity increased in CD44- cells. Ongoing analysis may elucidate the molecular mechanisms controlling the different cancer stem cell fates and their androgen sensitivity. Cancer stem cell potential of the different cell populations will have to be elucidated by transplantation experiments. Citation Format: Sofia Karkampouna, Marta de Menna, Markus Germann, Jöel Grosjean, Peter C. Gray, George N. Thalmann, Marianna Kruithof-de Julio. Molecular characterization of cancer stem cells from patient-derived xenografts of advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B060.
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- 2018
23. Erratum: Metastases in Prostate Cancer
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George N. Thalmann, Janine Hensel, Marianna Kruithof-de Julio, Marta De Menna, Federico La Manna, Sofia Karkampouna, and Eugenio Zoni
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Oncology ,medicine.medical_specialty ,Prostate cancer ,Text mining ,business.industry ,Internal medicine ,medicine ,medicine.disease ,business ,General Biochemistry, Genetics and Molecular Biology - Published
- 2018
24. Abstract 3053: Characterization of cancer stem cell subpopulations from patient-derived xenografts of advanced prostate cancer
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Marta De Menna, Peter Clark Gray, Joel Grosjean, Sofia Karkampouna, George N. Thalmann, Markus Germann, and Marianna Kruithof-de Julio
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Cancer Research ,biology ,CD44 ,Cancer ,urologic and male genital diseases ,medicine.disease ,Stem cell marker ,Androgen receptor ,Prostate cancer ,chemistry.chemical_compound ,Oncology ,chemistry ,Cancer stem cell ,biology.protein ,Cancer research ,medicine ,Enzalutamide ,Progenitor cell - Abstract
Androgen-deprivation therapy is the standard treatment for prostate cancer. Despite the initial response, a fraction of cases manifest progression to castration-resistant prostate cancer. PCa recurrence is possibly due to androgen-independent cancer stem cells that reinitiate tumor growth. The properties of cancer stem cells versus highly proliferative progenitor cells remain to be further characterized at the cellular and gene expression level. To address the molecular basis of CSC switch from androgen dependency to independence, we have employed patient-derived xenograft models (LAPC-9 and BM-18) that have different androgen sensitivity properties. We have performed microarray and proteomic analysis of BM-18 tumor tissues prior to and following castration as well as androgen replacement. To characterize the cancer stem cells in these models we have isolated different subpopulations by FACS cytometry, based on combination of selected markers (CD44 and ALDH activity measured by ALDELFUOR assay) aiming to assess the transcriptomic profile of these different populations. To assess response of these CD44+/-/ALDH+/- cells to androgen targeting compounds we have established an androgen-sensitive xenograft model (PNPCa) and tested it by ex vivo tissue culture and organoid viability assays. Proteomic and microarray analysis of bulk BM-18 tumors indicates enrichment of stem cell markers upon castration: CD44, NKX3.1 and ALDH1 isoforms. Readministration of testosterone induces decrease of these markers. Castration induces a rapid tumor volume decrease in the BM-18 as opposed to LAPC-9, reflecting different androgen-dependent cell states. CD44+/-/ALDHhigh/low subpopulations were isolated by flow cytometry and for transcriptomic analysis. Castration in the BM18 model induces an increase in the subpopulations of CD44+/ALDHlow and CD44+/ALDHhigh, while ALDHsingle and ALDHhigh total populations are decreased. Both CD44 expression and ALDH activity is increased in the LAPC-9 model upon castration. Treatment of PNPCa tumor parts ex vivo with enzalutamide inhibited expression of androgen receptor and keratin 8 expression. CD44+ organoids derived from the same tissue did not show altered viability after enzalutamide treatment. Different androgen-independent cancer stem cell populations may be distinguished by ALDH activity status and CD44. Androgen-independent cells in the BM-18 androgen-dependent model are reflected by enrichment of CD44 expression. The least abundant subpopulation CD44+/ALDHhigh is present in the LAPC-9 and expanded upon castration, while in the BM-18 model it is exclusively present after castration, reflecting different androgen sensitivity. Ongoing analysis may elucidate the molecular mechanisms controlling cancer stem cell fates, androgen sensitivity and drug resistance. Citation Format: Sofia Karkampouna, Marta De Menna, Markus Germann, Joel Grosjean, Peter Clark Gray, George Niklaus Thalmann, Marianna Kruithof-de Julio. Characterization of cancer stem cell subpopulations from patient-derived xenografts of advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3053.
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- 2018
25. Metastases in Prostate Cancer
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Janine Hensel, Federico La Manna, Marta De Menna, George N. Thalmann, Eugenio Zoni, Sofia Karkampouna, and Marianna Kruithof-de Julio
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Male ,0301 basic medicine ,Neoplasm, Residual ,Bone Neoplasms ,Soft Tissue Neoplasms ,Translational research ,Tumor cells ,Disease ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Metastatic cell ,Metastatic niche ,Tumor Microenvironment ,Animals ,Humans ,Medicine ,Neoplasm ,Neoplasm Metastasis ,610 Medicine & health ,business.industry ,Prostatic Neoplasms ,Neoplastic Cells, Circulating ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Erratum ,business ,Perspectives - Abstract
Prostate cancer (PCa) prognosis and clinical outcome is directly dependent on metastatic occurrence. The bone microenvironment is a favorable metastatic niche. Different biological processes have been suggested to contribute to the osteotropism of PCa such as hemodynamics, bone-specific signaling interactions, and the "seed and soil" hypothesis. However, prevalence of disseminating tumor cells in the bone is not proportional to the actual occurrence of metastases, as not all patients will develop bone metastases. The fate and tumor-reforming ability of a metastatic cell is greatly influenced by the microenvironment. In this review, the molecular mechanisms of bone and soft-tissue metastasis in PCa are discussed. Specific attention is dedicated to the residual disease, novel approaches, and animal models used in oncological translational research are illustrated.
- Published
- 2018
26. Molecular characterization of cancer stem cells from patient derived xenografts of advanced prostate cancer
- Author
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Joel Grosjean, Markus Germann, M. Kruithof-De Julio, Peter Clark Gray, Sofia Karkampouna, M. De Menna, and G.N. Thalmann
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Prostate cancer ,business.industry ,Cancer stem cell ,Urology ,medicine ,Cancer research ,medicine.disease ,business - Published
- 2018
27. Effects of ALK1Fc treatment on prostate cancer cells interacting with bone and bone cells in bone metastasis models
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Martin Spahn, Peter ten Dijke, Joel Grosjean, Marianna Kruithof-de Julio, George N. Thalmann, Irena Klima, Lukas J. A. C. Hawinkels, Marie-José Goumans, Letizia Astrologo, Sofia Karkampouna, Eugenio Zoni, Peter C. Gray, and Gabri van der Pluijm
- Subjects
Cancer Research ,Prostate cancer ,Oncology ,business.industry ,Bone cell ,medicine ,Cancer research ,Bone metastasis ,Cancer ,medicine.disease ,business ,Primary tumor ,Metastasis - Abstract
e16576 Background: Prostate cancer is the second most common cancer in men worldwide. Lethality is normally associated with the consequences of metastasis rather than the primary tumor. In particular, bone is the most frequent site of metastasis and once prostate tumor cells are engrafted in the skeleton, curative therapy is no longer possible. Bone morphogenetic proteins (BMPs) play a critical role in bone physiology and pathology. However, little is known about the role of BMP9 and its signaling receptors, ALK1 and ALK2, in prostate cancer and bone metastasis. In this context, we investigate the impact of BMP9 on primary prostate cancer and derived bone metastasis. Methods: The human ALK1 extracellular domain (ECD) binds BMP9 and BMP10 with high affinity. In order to study the effect of BMP9 in vitro and in vivo we use a soluble chimeric protein, consisting of ALK1 ECD fused to human Fc (ALK1Fc), for preventing the activation of endogenous signaling. ALK1Fc sequesters BMP9 and BMP10, preserving the activation of ALK1 through other ligands. Results: We show that ALK1Fc reduces BMP9-mediated signaling and decreases proliferation of highly metastatic and tumor initiating human prostate cancer cells in vitro. In line with these observations, we demonstrate that ALK1Fc reduces tumor growth in vivo in an orthotopic transplantation model. The propensity of the primary prostate cancer to metastasize to the bone is also investigated. In particular, we report how the ALK1Fc influences the prostate cancer cells in vitro and in vivo when these are probed in different bone settings (co-culture with bone cells and intraosseous transplantation in mice). Conclusions: Our study provides the first demonstration that ALK1Fc inhibits prostate cancer cells growth identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. All together, these findings justify the ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.
- Published
- 2017
28. Stroma transcriptomic and proteomic profile of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures
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Per Haberkant, George N. Thalmann, Frank Stein, De Filippo M, de Julio M, Eugenio Zoni, Irena Klima, Sofia Karkampouna, Charlotte K.Y. Ng, and Martin Spahn
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0303 health sciences ,Stromal cell ,Tissue microarray ,Bone metastasis ,Biology ,medicine.disease ,3. Good health ,Metastasis ,Transcriptome ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Stroma ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,030304 developmental biology - Abstract
Prostate cancer (PCa) is the second leading cause of cancer-associated death in men with therapy resistance acquisition to androgen deprivation treatment and metastasis progression. Understanding the mechanisms of tumor progression to metastatic stage is necessary for the design of therapeutic and prognostic schemes. The main objective of the current study is to determine, using transcriptomic and proteomic analyses on patient derived-xenograft models, whether differentially aggressive PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern, and how this information could be applied in prognostics. Transcriptomic profiling (RNA Sequencing) was performed on PCa PDX models representing different disease stages; BM18 (androgen dependent bone metastasis) and LAPC9 (androgen independent bone metastasis). Using organism-specific reference databases, the human-specific transcriptome, representing the tumor, was identified and separated from the mouse-specific transcriptome (representing the contributing stroma counterpart) from the same PDX tumor samples. To identify proteome changes in the tumor (human) versus the stroma (mouse), we performed human and mouse cell separation using the MACS mouse depletion sorting kit, and subjected protein lysates to quantitative TMT labeling and mass spectrometry. We show that tenascin C is one of the most abundant stromal genes in bone metastasis PCa PDXs, is modulated by androgen levelsin vivoand is highly expressed in castration resistant LAPC9 PDX compared to castration sensitive BM18 PDX. Tissue microarray of primary PCa samples (N=210) was used to evaluate the potential of TNC to act as a metastasis prognosis marker. Low number of TNC-positive cells were associated with statistically significant clinical progression to local recurrence or metastasis, compared to high TNC-positive group. Our data showed that metastatic PCa PDXs that differ in androgen sensitivity trigger a differential stroma response suggesting that stroma was influenced by tumor cues. Selected stromal markers of osteoblastic PCa induced bone metastases, were induced in the microenvironment of the host organism in metastatic xenografts, although implanted in a non-bone site, indicating a conserved mechanism of tumor cells to induce a stromal pre-metastatic signature with high potential prognostic or diagnostic value.
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