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1. Three-dimensional imaging mass cytometry for highly multiplexed molecular and cellular mapping of tissues and the tumor microenvironment

Author

Kuett, Laura, Catena, Raúl, Özcan, Alaz, Plüss, Alex, Ali, H. R., Sa’d, M. Al, Alon, S., Aparicio, S., Battistoni, G., Balasubramanian, S., Becker, R., Bodenmiller, B., Boyden, E. S., Bressan, D., Bruna, A., Burger, Marcel, Caldas, C., Callari, M., Cannell, I. G., Casbolt, H., Chornay, N., Cui, Y., Dariush, A., Dinh, K., Emenari, A., Eyal-Lubling, Y., Fan, J., Fatemi, A., Fisher, E., González-Solares, E. A., González-Fernández, C., Goodwin, D., Greenwood, W., Grimaldi, F., Hannon, G. J., Harris, S., Jauset, C., Joyce, J. A., Karagiannis, E. D., Kovačević, T., Kuett, L., Kunes, R., Yoldaş, A. Küpcü, Lai, D., Laks, E., Lee, H., Lee, M., Lerda, G., Li, Y., McPherson, A., Millar, N., Mulvey, C. M., Nugent, I., O’Flanagan, C. H., Paez-Ribes, M., Pearsall, I., Qosaj, F., Roth, A. J., Rueda, O. M., Ruiz, T., Sawicka, K., Sepúlveda, L. A., Shah, S. P., Shea, A., Sinha, A., Smith, A., Tavaré, S., Tietscher, S., Vázquez-García, I., Vogl, S. L., Walton, N. A., Wassie, A. T., Watson, S. S., Weselak, J., Wild, S. A., Williams, E., Windhager, J., Xia, C., Zheng, P., Zhuang, X., Schraml, Peter, Moch, Holger, de Souza, Natalie, and Bodenmiller, Bernd

Subjects
Cancer Research, Oncology
Abstract

A holistic understanding of tissue and organ structure and function requires the detection of molecular constituents in their original three-dimensional (3D) context. Imaging mass cytometry (IMC) enables simultaneous detection of up to 40 antigens and transcripts using metal-tagged antibodies but has so far been restricted to two-dimensional imaging. Here we report the development of 3D IMC for multiplexed 3D tissue analysis at single-cell resolution and demonstrate the utility of the technology by analysis of human breast cancer samples. The resulting 3D models reveal cellular and microenvironmental heterogeneity and cell-level tissue organization not detectable in two dimensions. 3D IMC will prove powerful in the study of phenomena occurring in 3D space such as tumor cell invasion and is expected to provide invaluable insights into cellular microenvironments and tissue architecture.

Published
2021
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2. Three-dimensional imaging mass cytometry for highly multiplexed molecular and cellular mapping of tissues and the tumor microenvironment

Author

Kuett, L, Catena, R, ��zcan, A, Pl��ss, A, Ali, HR, Sa���d, MA, Alon, S, Aparicio, S, Battistoni, G, Balasubramanian, Shankar, Becker, R, Bodenmiller, B, Boyden, ES, Bressan, D, Bruna, A, Burger, M, Caldas, Carlos, Callari, M, Cannell, IG, Casbolt, H, Chornay, N, Cui, Y, Dariush, Aliakbar, Dinh, K, Emenari, A, Eyal-Lubling, Y, Fan, J, Fatemi, A, Fisher, E, Gonz��lez-Solares, EA, Gonz��lez-Fern��ndez, C, Goodwin, D, Greenwood, W, Grimaldi, F, Hannon, GJ, Harris, S, Jauset, C, Joyce, JA, Karagiannis, ED, Kova��evi��, T, Kunes, R, Yolda��, AK, Lai, D, Laks, E, Lee, H, Lee, M, Lerda, G, Li, Y, McPherson, A, Millar, N, Mulvey, CM, Nugent, I, O���Flanagan, CH, Paez-Ribes, M, Pearsall, I, Qosaj, F, Roth, AJ, Rueda, OM, Ruiz, T, Sawicka, K, Sep��lveda, LA, Shah, SP, Shea, A, Sinha, A, Smith, A, Tavar��, S, Tietscher, S, V��zquez-Garc��a, I, Vogl, SL, Walton, NA, Wassie, AT, Watson, SS, Weselak, J, Wild, SA, Williams, E, Windhager, J, Xia, C, Zheng, P, Zhuang, X, Schraml, P, Moch, H, De Souza, N, Ali, Raza [0000-0001-7587-0906], Balasubramanian, Shankar [0000-0002-0281-5815], Caldas, Carlos [0000-0003-3547-1489], Hannon, Gregory [0000-0003-4021-3898], Walton, Nicholas [0000-0003-3983-8778], and Apollo - University of Cambridge Repository

Subjects
Imaging, Three-Dimensional, Tumor Microenvironment, Humans, Breast Neoplasms, Female, Antibodies, Image Cytometry
Abstract

A holistic understanding of tissue and organ structure and function requires the detection of molecular constituents in their original three-dimensional (3D) context. Imaging mass cytometry (IMC) enables simultaneous detection of up to 40 antigens and transcripts using metal-tagged antibodies but has so far been restricted to two-dimensional imaging. Here we report the development of 3D IMC for multiplexed 3D tissue analysis at single-cell resolution and demonstrate the utility of the technology by analysis of human breast cancer samples. The resulting 3D models reveal cellular and microenvironmental heterogeneity and cell-level tissue organization not detectable in two dimensions. 3D IMC will prove powerful in the study of phenomena occurring in 3D space such as tumor cell invasion and is expected to provide invaluable insights into cellular microenvironments and tissue architecture.

Published
2022

3. Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response

Author

Georgopoulou, Dimitra, Callari, Maurizio, Rueda, Oscar M., Shea, Abigail, Martin, Alistair, Giovannetti, Agnese, Qosaj, Fatime, Dariush, Ali, Chin, Suet-Feung, Carnevalli, Larissa S., Provenzano, Elena, Greenwood, Wendy, Lerda, Giulia, Esmaeilishirazifard, Elham, O’Reilly, Martin, Serra, Violeta, Bressan, Dario, Mills, Gordon B., Ali, H. Raza, Cosulich, Sabina S., Hannon, Gregory J., Bruna, Alejandra, Caldas, Carlos, Ali, H. R., Al Sa’d, M., Alon, S., Aparicio, S., Battistoni, G., Balasubramanian, S., Becker, R., Bodenmiller, B., Boyden, E. S., Bressan, D., Bruna, A., Burger, Marcel, Caldas, C., Callari, M., Cannell, I. G., Casbolt, H., Chornay, N., Cui, Y., Dariush, A., Dinh, K., Emenari, A., Eyal-Lubling, Y., Fan, J., Fatemi, A., Fisher, E., González-Solares, E. A., González-Fernández, C., Goodwin, D., Greenwood, W., Grimaldi, F., Hannon, G. J., Harris, O., Harris, S., Jauset, C., Joyce, J. A., Karagiannis, E. D., Kovačević, T., Kuett, L., Kunes, R., Küpcü, Yoldaş A., Lai, D., Laks, E., Lee, H., Lee, M., Lerda, G., Li, Y., McPherson, A., Millar, N., Mulvey, C. M., Nugent, F., O’Flanagan, C. H., Paez-Ribes, M., Pearsall, I., Qosaj, F., Roth, A. J., Rueda, O. M., Ruiz, T., Sawicka, K., Sepúlveda, L. A., Shah, S. P., Shea, A., Sinha, A., Smith, A., Tavaré, S., Tietscher, S., Vázquez-García, I., Vogl, S. L., Walton, N. A., Wassie, A. T., Watson, S. S., Weselak, J., Wild, S. A., Williams, E., Windhager, J., Whitmarsh, T., Xia, C., Zheng, P., Zhuang, X., Rueda, Oscar M. [0000-0003-0008-4884], Giovannetti, Agnese [0000-0001-5207-7243], Chin, Suet-Feung [0000-0001-5697-1082], Carnevalli, Larissa S. [0000-0001-7432-0195], Provenzano, Elena [0000-0003-3345-3965], Serra, Violeta [0000-0001-6620-1065], Bressan, Dario [0000-0003-3592-699X], Mills, Gordon B. [0000-0002-0144-9614], Ali, H. Raza [0000-0001-7587-0906], Caldas, Carlos [0000-0003-3547-1489], and Apollo - University of Cambridge Repository

Subjects
13/1, 13/105, article, 13/106, 38/39, 45/23, 631/67/1347, 631/67/2329
Abstract

Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Funder: AstraZeneca; doi: https://doi.org/10.13039/100004325, The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.

Published
2021
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4. Mechanisms of responsiveness to and resistance against trabectedin in murine models of human myxoid liposarcoma

Author

Paolo G. Casali, Roberta Sanfilippo, M. D'Incalci, Maurizio Callari, Marta Barisella, Marina Meroni, Roberta Frapolli, Chiara Fabbroni, Ilaria Craparotta, Nicolò Panini, Laura Mannarino, Sergio Marchini, Sara Ballabio, Ezia Bello, Mannarino, L, Craparotta, I, Ballabio, S, Frapolli, R, Meroni, M, Bello, E, Panini, N, Callari, M, Sanfilippo, R, Casali, P, Barisella, M, Fabbroni, C, Marchini, S, and D'Incalci, M

Subjects
Adult, Myxoid liposarcoma, Trabectedin, PDX, Data integration, RNA-Seq, DNA-Seq, Biology, Transcriptome, Mice, Chimera (genetics), Genetics, medicine, Transcriptional regulation, Animals, Humans, RNA-Seq, Gene, Trabectedin, PDX, Myxoid liposarcoma, medicine.disease, Liposarcoma, Myxoid, Disease Models, Animal, Mechanism of action, Cancer research, Data integration, Sarcoma, medicine.symptom, DNA-Seq, medicine.drug
Abstract

Myxoid liposarcoma (MLPS) is a rare soft-tissue sarcoma characterised by the expression of FUS-DDIT3 chimera. Trabectedin has shown significant clinical anti-tumour activity against MLPS. To characterise the molecular mechanism of trabectedin sensitivity and of resistance against it, we integrated genomic and transcriptomic data from treated mice bearing ML017 or ML017/ET, two patient-derived MLPS xenograft models, sensitive to and resistant against trabectedin, respectively. Longitudinal RNA-Seq analysis of ML017 showed that trabectedin acts mainly as a transcriptional regulator: 15 days after the third dose trabectedin modulates the transcription of 4883 genes involved in processes that sustain adipocyte differentiation. No such differences were observed in ML017/ET. Genomic analysis showed that prolonged treatment causes losses in 4p15.2, 4p16.3 and 17q21.3 cytobands leading to acquired-resistance against the drug. The results dissect the complex mechanism of action of trabectedin and provide the basis for novel combinatorial approaches for the treatment of MLPS that could overcome drug-resistance.

Published
2021
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5. Next Generation-Targeted Amplicon Sequencing (NG-TAS): an optimised protocol and computational pipeline for cost-effective profiling of circulating tumour DNA

Author

Institut Català de la Salut, [Gao M, Callari M] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. [Beddowes E] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. Breast Cancer Programme, Cancer Research UK Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. [Sammut SJ, Grzelak M] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. [Biggs H] Breast Cancer Programme, Cancer Research UK Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. [Cortes J] Ramon y Cajal University Hospital, Madrid, Spain. Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. [Oliveira M] Vall d'Hebron Institut d'Oncologia, Barcelona, Spain., and Hospital Universitari Vall d'Hebron

Subjects
Neoplasms [DISEASES], Other subheadings::/methods [Other subheadings], técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Otros calificadores::/métodos [Otros calificadores], Neoplasias [ENFERMEDADES], Ciencia de la Información::Metodologias Computacionales [CIENCIA DE LA INFORMACIÓN], ADN - Anàlisi, Càncer, Biologia computacional, Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT], Information Science::Computing Methodologies [INFORMATION SCIENCE]
Published
2021

6. Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response

Author

Sabina S Cosulich, Abigail Shea, Maurizio Callari, A. Dariush, Elena Provenzano, Martin O'Reilly, Carlos Caldas, Dimitra Georgopoulou, Agnese Giovannetti, Oscar M. Rueda, Gregory J. Hannon, Suet-Feung Chin, Giulia Lerda, Elham Esmaeilishirazifard, Alistair Martin, Violeta Serra, Fatime Qosaj, Wendy Greenwood, Dario Bressan, Larissa S. Carnevalli, Alejandra Bruna, H. Raza Ali, Gordon B. Mills, Rueda, Oscar M [0000-0003-0008-4884], Giovannetti, Agnese [0000-0001-5207-7243], Chin, Suet-Feung [0000-0001-5697-1082], Carnevalli, Larissa S [0000-0001-7432-0195], Provenzano, Elena [0000-0003-3345-3965], Serra, Violeta [0000-0001-6620-1065], Bressan, Dario [0000-0003-3592-699X], Mills, Gordon B [0000-0002-0144-9614], Ali, H Raza [0000-0001-7587-0906], Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository, IMAXT Consortium, Ali, H.R., Al Sa'd, M., Alon, S., Aparicio, S., Battistoni, G., Balasubramanian, S., Becker, R., Bodenmiller, B., Boyden, E.S., Bressan, D., Bruna, A., Burger, M., Caldas, C., Callari, M., Cannell, I.G., Casbolt, H., Chornay, N., Cui, Y., Dariush, A., Dinh, K., Emenari, A., Eyal-Lubling, Y., Fan, J., Fatemi, A., Fisher, E., González-Solares, E.A., González-Fernández, C., Goodwin, D., Greenwood, W., Grimaldi, F., Hannon, G.J., Harris, O., Harris, S., Jauset, C., Joyce, J.A., Karagiannis, E.D., Kovačević, T., Kuett, L., Kunes, R., Küpcü, Y.A., Lai, D., Laks, E., Lee, H., Lee, M., Lerda, G., Li, Y., McPherson, A., Millar, N., Mulvey, C.M., Nugent, F., O'Flanagan, C.H., Paez-Ribes, M., Pearsall, I., Qosaj, F., Roth, A.J., Rueda, O.M., Ruiz, T., Sawicka, K., Sepúlveda, L.A., Shah, S.P., Shea, A., Sinha, A., Smith, A., Tavaré, S., Tietscher, S., Vázquez-García, I., Vogl, S.L., Walton, N.A., Wassie, A.T., Watson, S.S., Weselak, J., Wild, S.A., Williams, E., Windhager, J., Whitmarsh, T., Xia, C., Zheng, P., and Zhuang, X.

Subjects
0301 basic medicine, Pyridines, Science, Tumour heterogeneity, Morpholines, Cell, General Physics and Astronomy, Breast Neoplasms, Drug resistance, Mice, SCID, Biology, Animals, Benzamides/pharmacology, Breast Neoplasms/drug therapy, Breast Neoplasms/genetics, Breast Neoplasms/metabolism, Cell Line, Tumor, Drug Resistance, Neoplasm/drug effects, Drug Resistance, Neoplasm/genetics, Female, Heterografts/drug effects, Heterografts/metabolism, Humans, MCF-7 Cells, Mice, Inbred NOD, Mice, Knockout, Morpholines/pharmacology, Piperazines/pharmacology, Protein Kinase Inhibitors/pharmacology, Pyridines/pharmacology, Pyrimidines/pharmacology, Treatment Outcome, Xenograft Model Antitumor Assays/methods, General Biochemistry, Genetics and Molecular Biology, Article, Piperazines, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Mass cytometry, Protein Kinase Inhibitors, Multidisciplinary, Genetic heterogeneity, Cancer, General Chemistry, medicine.disease, Biobank, Phenotype, Xenograft Model Antitumor Assays, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Pyrimidines, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Benzamides, Cancer research, Heterografts
Abstract

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance., The heterogeneity of breast cancer has a major role in drug response and resistance. In this study, the authors use patient-derived tumour xenografts as a platform for drug testing and correlation with single-cell proteomic phenotypes characterized by mass cytometry.

Published
2021
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7. Next Generation-Targeted Amplicon Sequencing (NG-TAS): An optimised protocol and computational pipeline for cost-effective profiling of circulating tumour DNA

Author

Maurizio Callari, Suet-Feung Chin, Mafalda Oliveira, Richard D. Baird, Carlos Caldas, Javier Cortés, Marta Grzelak, Heather Biggs, Emma Beddowes, Stephen John Sammut, Sabine C. Linn, Meiling Gao, Linda Jones, Abdelhamid Boumertit, Beddowes, Emma [0000-0001-7649-2863], Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Gao M, Callari M] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. [Beddowes E] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. Breast Cancer Programme, Cancer Research UK Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. [Sammut SJ, Grzelak M] Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. [Biggs H] Breast Cancer Programme, Cancer Research UK Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. [Cortes J] Ramon y Cajal University Hospital, Madrid, Spain. Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. [Oliveira M] Vall d'Hebron Institut d'Oncologia, Barcelona, Spain., Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, Callari, Maurizio [0000-0001-5239-0918], Sammut, Stephen [0000-0003-4472-904X], Jones, Linda [0000-0001-9347-5715], Baird, Richard [0000-0001-7071-6483], and Chin, Suet-Feung [0000-0001-5697-1082]

Subjects
0301 basic medicine, Other subheadings::/methods [Other subheadings], Deep sequencing, lcsh:Medicine, Method, 32 Biomedical and Clinical Sciences, Multiplexing, Circulating Tumor DNA, chemistry.chemical_compound, 0302 clinical medicine, Otros calificadores::/métodos [Otros calificadores], NG-TAS, International HapMap Project, Càncer, Genetics (clinical), Cancer, 0303 health sciences, High-Throughput Nucleotide Sequencing, 3 Good Health and Well Being, Amplicon, 3. Good health, Plasma.cfDNA, 030220 oncology & carcinogenesis, Costs and Cost Analysis, Amplicon sequencing, Molecular Medicine, Cancer gene, Female, ADN - Anàlisi, Ciencias de la información::metodologías computacionales [CIENCIA DE LA INFORMACIÓN], Técnicas de Investigación::Técnicas Genéticas::Análisis de Secuencia::Análisis de Secuencia de ADN [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], animal structures, lcsh:QH426-470, técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Computational biology, Biology, Biologia computacional, Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT], neoplasias [ENFERMEDADES], 03 medical and health sciences, Clinical Research, Cell Line, Tumor, Breast Cancer, Genetics, Biomarkers, Tumor, Humans, Genetic Testing, Heterogeneous, Liquid biopsy, Allele, Molecular Biology, Gene, Information Science::Computing Methodologies [INFORMATION SCIENCE], 030304 developmental biology, lcsh:R, Human Genome, Computational pipeline, ctDNA, Sequence Analysis, DNA, 3211 Oncology and Carcinogenesis, Human genetics, 4.1 Discovery and preclinical testing of markers and technologies, Neoplasms [DISEASES], lcsh:Genetics, 030104 developmental biology, chemistry, Mutation, Ciencia de la Información::Metodologias Computacionales [CIENCIA DE LA INFORMACIÓN], 4 Detection, screening and diagnosis, Software, DNA, 31 Biological Sciences
Abstract

Circulating tumour DNA (ctDNA) detection and monitoring has enormous potential clinical utility in oncology. We describe here a fast, flexible and cost-effective method to profile multiple genes simultaneously in low input cell-free DNA (cfDNA): Next Generation-Targeted Amplicon Sequencing (NG-TAS). We designed a panel of 377 amplicons spanning 20 cancer genes and tested the NG-TAS pipeline using cell-free DNA from two hapmap lymphoblastoid cell lines. NG-TAS consistently detected mutations in cfDNA when mutation allele fraction was >1%. We applied NG-TAS to a clinical cohort of metastatic breast cancer patients, demonstrating its potential in monitoring the disease. The computational pipeline is available at: https://github.com/cclab-brca/NGTAS_pipeline.

Published
2018
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8. miR-205 regulates basement membrane deposition in human prostate: implications for cancer development

Author

Marco Folini, Paolo Gandellini, Anna Casamichele, Maurizio Colecchia, Nicola Fenderico, Maurizio Callari, Riccardo Valdagni, Silvia Pozzi, M. De Cesare, G Santilli, S. Borrelli, Valentina Profumo, Roberto Mantovani, Nadia Zaffaroni, Giulia Petrovich, Gandellini, P, Profumo, V, Casamichele, A, Fenderico, N, Borrelli, S, Petrovich, G, Santilli, G, Callari, M, Colecchia, M, Pozzi, S, De Cesare, M, Folini, M, Valdagni, R, Mantovani, R, and Zaffaroni, N

Subjects
Male, Pathology, medicine.medical_specialty, Transcription, Genetic, Biology, medicine.disease_cause, Basement Membrane, Cell Line, Metastasis, Extracellular matrix, Prostate cancer, Prostate, microRNA, medicine, Humans, Promoter Regions, Genetic, Molecular Biology, Basement membrane, Original Paper, Tumor Suppressor Proteins, Integrin beta4, Cell Biology, medicine.disease, Epithelium, Cell biology, MicroRNAs, Cell Transformation, Neoplastic, medicine.anatomical_structure, Carcinogenesis, Cell Adhesion Molecules, Transcription Factors
Abstract

The basement membrane (BM) is a layer of specialized extracellular matrix that surrounds normal prostate glands and preserves tissue integrity. Lack or discontinuity of the BM is a prerequisite for tumor cell invasion into interstitial spaces, thus favoring metastasis. Therefore, BM maintenance represents a barrier against cancer development and progression. In the study, we show that miR-205 participates in a network involving ΔNp63α, which is essential for maintenance of the BM in prostate epithelium. At the molecular level, ΔNp63α is able to enhance miR-205 transcription by binding to its promoter, whereas the microRNA can post-transcriptionally limit the amount of ΔNp63α protein, mostly by affecting ΔNp63α proteasomal degradation rather than through a canonical miRNA/target interaction. Functionally, miR-205 is able to control the deposition of laminin-332 and its receptor integrin-β4. Hence, pathological loss of miR-205, as widely observed in prostate cancer, may favor tumorigenesis by creating discontinuities in the BM. Here we demonstrate that therapeutic replacement of miR-205 in prostate cancer (PCa) cells can restore BM deposition and 3D organization into normal-like acinar structures, thus hampering cancer progression.

Published
2012
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9. By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy

Author

Adriana Cordova, Flora Iovino, Matilde Todaro, Marilisa Cargnelutti, Laura Rosa Mangiapane, Maurizio Callari, R. Carollo, Silvia Giordano, Alessandro Giammona, Giorgio Stassi, Maria Grazia Daidone, Filippo Montemurro, Daniela Taverna, Daniela Cimino, Annalisa Petrelli, Petrelli, A, Carollo, R, Cargnelutti, M, Iovino, F, Callari, M, Cimino, D, Todaro, M, Mangiapane, LR, Giammona, A, Cordova, A, Montemurro, F, Taverna, D, Daidone, MG, Stassi, G, and Giordano S

Subjects
Oncology, CA15-3, medicine.medical_specialty, Pathology, Breast cancer, basal-like, differentiation, miR-100, Cancer, Estrogen receptor, differentiation, Biology, breast cancer, Basal-like, mir-100, medicine.disease, basal-like, miR-100, Transplantation, Breast cancer, Internal medicine, medicine, Hormonal therapy, Stem cell, Tamoxifen, medicine.drug, Research Paper
Abstract

// Annalisa Petrelli 1,* , Rosachiara Carollo 2,* , Marilisa Cargnelutti 1 , Flora Iovino 2 , Maurizio Callari 3 , Daniela Cimino 4 , Matilde Todaro 2 , Laura Rosa Mangiapane 2 , Alessandro Giammona 2 , Adriana Cordova 2 , Filippo Montemurro 1 , Daniela Taverna 4 , Maria Grazia Daidone 3 , Giorgio Stassi 2,* and Silvia Giordano 1,* 1 University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS, Str. Provinciale, Candiolo, Torino, Italy 2 Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy 3 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 4 Molecular Biotechnology Center (MBC), Department of Oncological Sciences, Center for Molecular Systems Biology, Via Nizza, University of Torino, Torino, Italy * These authors contributed equally to this work Correspondence: Silvia Giordano, email: // Giorgio Stassi, email: // Annalisa Petrelli, email: // Keywords : Breast cancer, basal-like, differentiation, miR-100 Received : September 30, 2014 Accepted : December 10, 2014 Published : December 11, 2014 Abstract Basal-like breast cancer is an aggressive tumor subtype with a poor response to conventional therapies. Tumor formation and relapse are sustained by a cell subset of Breast Cancer Stem Cells (BrCSCs). Here we show that miR-100 inhibits maintenance and expansion of BrCSCs in basal-like cancer through Polo-like kinase1 (Plk1) down-regulation. Moreover, miR-100 favors BrCSC differentiation, converting a basal like phenotype into luminal. It induces the expression of a functional estrogen receptor (ER) and renders basal-like BrCSCs responsive to hormonal therapy. The key role played by miR-100 in breast cancer free-survival is confirmed by the analysis of a cohort of patients’ tumors, which shows that low expression of miR-100 is a negative prognostic factor and is associated with gene signatures of high grade undifferentiated tumors. Our findings indicate a new possible therapeutic strategy, which could make aggressive breast cancers responsive to standard treatments.

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