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31 results on '"Werb, Zena"'

1. Single-cell analysis of breast cancer metastasis reveals epithelial-mesenchymal plasticity signatures associated with poor outcomes

Author

Winkler, Juliane, Tan, Weilun, Diadhiou, Catherine M.M., McGinnis, Christopher S., Abbasi, Aamna, Hasnain, Saad, Durney, Sophia, Atamaniuc, Elena, Superville, Daphne, Awni, Leena, Lee, Joyce V., Hinrichs, Johanna H., Wagner, Patrick S., Singh, Namrata, Hein, Marco Y., Borja, Michael, Detweiler, Angela M., Liu, Su- Yang, Nanjaraj, Ankitha, Sitarama, Vaishnavi, Rugo, Hope S., Neff, Norma, Gartner, Zev J., Pisco, Angela Oliveira, Goga, Andrei, Darmanis, Spyros, and Werb, Zena

Subjects
Physiological aspects, Patient outcomes, Health aspects, Cancer research, Cancer cells -- Physiological aspects, Physiological adaptation -- Health aspects, Stem cells -- Health aspects, Epithelial cells -- Health aspects, Breast cancer -- Physiological aspects -- Patient outcomes, Cancer metastasis -- Physiological aspects -- Patient outcomes, Oncology, Experimental, Metastasis -- Physiological aspects -- Patient outcomes, Adaptation (Physiology) -- Health aspects, Cancer -- Research
Abstract

Introduction Metastases account for the vast majority of cancer-related deaths (1), however, why some cancers metastasize while others do not is poorly understood. Specific genetic alterations do not define metastatic [...], Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.

Published
2024
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2. Bisphenol A replacement chemicals, BPF and BPS, induce protumorigenic changes in human mammary gland organoid morphology and proteome

Author

Winkler, Juliane, Liu, Pengyuan, Phong, Kiet, Hinrichs, Johanna H, Ataii, Nassim, Williams, Katherine, Hadler-Olsen, Elin, Samson, Susan, Gartner, Zev J, Fisher, Susan, and Werb, Zena

Subjects
Environmental Sciences, Pollution and Contamination, Women's Health, Cancer, Breast Cancer, Good Health and Well Being, Benzhydryl Compounds, Carcinogenesis, Estrogens, Humans, Mammary Glands, Human, Organoids, Phenols, Proteome, Proteomics, Sulfones, bisphenols, mammary gland, organoids, proteomics, breast cancer, global proteomics
Abstract

SignificanceBisphenol A (BPA), found in many plastic products, has weak estrogenic effects that can be harmful to human health. Thus, structurally related replacements-bisphenol S (BPS) and bisphenol F (BPF)-are coming into wider use with very few data about their biological activities. Here, we compared the effects of BPA, BPS, and BPF on human mammary organoids established from normal breast tissue. BPS disrupted organoid architecture and induced supernumerary branching. At a proteomic level, the bisphenols altered the abundance of common targets and those that were unique to each compound. The latter included proteins linked to tumor-promoting processes. These data highlighted the importance of testing the human health effects of replacements that are structurally related to chemicals of concern.

Published
2022

3. Cellular architecture of human brain metastases

Author

Gonzalez, Hugo, Mei, Wenbin, Robles, Isabella, Hagerling, Catharina, Allen, Breanna M, Hauge Okholm, Trine Line, Nanjaraj, Ankitha, Verbeek, Tamara, Kalavacherla, Sandhya, van Gogh, Merel, Georgiou, Stephen, Daras, Mariza, Phillips, Joanna J, Spitzer, Matthew H, Roose, Jeroen P, and Werb, Zena

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Stem Cell Research - Nonembryonic - Human, Neurosciences, Stem Cell Research, Brain Disorders, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Adult, Aged, Animals, Biomarkers, Tumor, Brain Neoplasms, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Female, Genetic Variation, Humans, Immune Evasion, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Models, Biological, Myeloid Cells, Principal Component Analysis, RNA-Seq, Single-Cell Analysis, T-Lymphocytes, CyTOF, blood tumor barrier, human metastasis, metastasis-associated macrophages, metastasis-infiltrated T cells, metastatic niche, metastatic program, metastatic tumor cells, metastatic tumors, single cell, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and revealed stromal immunosuppressive states enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits.

Published
2022

4. LGL1 binds to Integrin β1 and inhibits downstream signaling to promote epithelial branching in the mammary gland

Author

Ma, Rongze, Gong, Difei, You, Huanyang, Xu, Chongshen, Lu, Yunzhe, Bergers, Gabriele, Werb, Zena, Klein, Ophir D, Petritsch, Claudia K, and Lu, Pengfei

Subjects
Biochemistry and Cell Biology, Biological Sciences, Breast Cancer, Cancer, Animals, Cell Movement, Cell Polarity, Cell Proliferation, Down-Regulation, Epithelial Cells, Epithelium, Female, Gene Expression Regulation, Neoplastic, Glycoproteins, Integrin beta1, Mammary Glands, Animal, Mice, Transgenic, Models, Biological, Morphogenesis, Protein Binding, Signal Transduction, branching morphogenesis, collective migration, epithelial migration, epithelial polarity, extracellular matrix, integrin signaling, tumor-suppressor genes, Medical Physiology, Biological sciences
Abstract

Branching morphogenesis is a fundamental process by which organs in invertebrates and vertebrates form branches to expand their surface areas. The current dogma holds that directional cell migration determines where a new branch forms and thus patterns branching. Here, we asked whether mouse Lgl1, a homolog of the Drosophila tumor suppressor Lgl, regulates epithelial polarity in the mammary gland. Surprisingly, mammary glands lacking Lgl1 have normal epithelial polarity, but they form fewer branches. Moreover, we find that Lgl1 null epithelium is unable to directionally migrate, suggesting that migration is not essential for mammary epithelial branching as expected. We show that LGL1 binds to Integrin β1 and inhibits its downstream signaling, and Integrin β1 overexpression blocks epithelial migration, thus recapitulating the Lgl1 null phenotype. Altogether, we demonstrate that Lgl1 modulation of Integrin β1 signaling is essential for directional migration and that epithelial branching in invertebrates and the mammary gland is fundamentally distinct.

Published
2022

5. Data from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

Author

Littlepage, Laurie E., primary, Adler, Adam S., primary, Kouros-Mehr, Hosein, primary, Huang, Guiqing, primary, Chou, Jonathan, primary, Krig, Sheryl R., primary, Griffith, Obi L., primary, Korkola, James E., primary, Qu, Kun, primary, Lawson, Devon A., primary, Xue, Qing, primary, Sternlicht, Mark D., primary, Dijkgraaf, Gerrit J.P., primary, Yaswen, Paul, primary, Rugo, Hope S., primary, Sweeney, Colleen A., primary, Collins, Colin C., primary, Gray, Joe W., primary, Chang, Howard Y., primary, and Werb, Zena, primary

Published
2023
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6. Supplementary Table 3 from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

Author

Littlepage, Laurie E., primary, Adler, Adam S., primary, Kouros-Mehr, Hosein, primary, Huang, Guiqing, primary, Chou, Jonathan, primary, Krig, Sheryl R., primary, Griffith, Obi L., primary, Korkola, James E., primary, Qu, Kun, primary, Lawson, Devon A., primary, Xue, Qing, primary, Sternlicht, Mark D., primary, Dijkgraaf, Gerrit J.P., primary, Yaswen, Paul, primary, Rugo, Hope S., primary, Sweeney, Colleen A., primary, Collins, Colin C., primary, Gray, Joe W., primary, Chang, Howard Y., primary, and Werb, Zena, primary

Published
2023
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7. Supplementary Table 4 from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

Author

Littlepage, Laurie E., primary, Adler, Adam S., primary, Kouros-Mehr, Hosein, primary, Huang, Guiqing, primary, Chou, Jonathan, primary, Krig, Sheryl R., primary, Griffith, Obi L., primary, Korkola, James E., primary, Qu, Kun, primary, Lawson, Devon A., primary, Xue, Qing, primary, Sternlicht, Mark D., primary, Dijkgraaf, Gerrit J.P., primary, Yaswen, Paul, primary, Rugo, Hope S., primary, Sweeney, Colleen A., primary, Collins, Colin C., primary, Gray, Joe W., primary, Chang, Howard Y., primary, and Werb, Zena, primary

Published
2023
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8. Supplementary Table 2 from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

Author

Littlepage, Laurie E., primary, Adler, Adam S., primary, Kouros-Mehr, Hosein, primary, Huang, Guiqing, primary, Chou, Jonathan, primary, Krig, Sheryl R., primary, Griffith, Obi L., primary, Korkola, James E., primary, Qu, Kun, primary, Lawson, Devon A., primary, Xue, Qing, primary, Sternlicht, Mark D., primary, Dijkgraaf, Gerrit J.P., primary, Yaswen, Paul, primary, Rugo, Hope S., primary, Sweeney, Colleen A., primary, Collins, Colin C., primary, Gray, Joe W., primary, Chang, Howard Y., primary, and Werb, Zena, primary

Published
2023
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9. Supplementary Table 5 from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

Author

Littlepage, Laurie E., primary, Adler, Adam S., primary, Kouros-Mehr, Hosein, primary, Huang, Guiqing, primary, Chou, Jonathan, primary, Krig, Sheryl R., primary, Griffith, Obi L., primary, Korkola, James E., primary, Qu, Kun, primary, Lawson, Devon A., primary, Xue, Qing, primary, Sternlicht, Mark D., primary, Dijkgraaf, Gerrit J.P., primary, Yaswen, Paul, primary, Rugo, Hope S., primary, Sweeney, Colleen A., primary, Collins, Colin C., primary, Gray, Joe W., primary, Chang, Howard Y., primary, and Werb, Zena, primary

Published
2023
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10. Supplementary Table 1 from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

Author

Littlepage, Laurie E., primary, Adler, Adam S., primary, Kouros-Mehr, Hosein, primary, Huang, Guiqing, primary, Chou, Jonathan, primary, Krig, Sheryl R., primary, Griffith, Obi L., primary, Korkola, James E., primary, Qu, Kun, primary, Lawson, Devon A., primary, Xue, Qing, primary, Sternlicht, Mark D., primary, Dijkgraaf, Gerrit J.P., primary, Yaswen, Paul, primary, Rugo, Hope S., primary, Sweeney, Colleen A., primary, Collins, Colin C., primary, Gray, Joe W., primary, Chang, Howard Y., primary, and Werb, Zena, primary

Published
2023
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11. Supplementary Materials and Methods from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

Author

Littlepage, Laurie E., primary, Adler, Adam S., primary, Kouros-Mehr, Hosein, primary, Huang, Guiqing, primary, Chou, Jonathan, primary, Krig, Sheryl R., primary, Griffith, Obi L., primary, Korkola, James E., primary, Qu, Kun, primary, Lawson, Devon A., primary, Xue, Qing, primary, Sternlicht, Mark D., primary, Dijkgraaf, Gerrit J.P., primary, Yaswen, Paul, primary, Rugo, Hope S., primary, Sweeney, Colleen A., primary, Collins, Colin C., primary, Gray, Joe W., primary, Chang, Howard Y., primary, and Werb, Zena, primary

Published
2023
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12. Supplementary Methods, Figures 1-4, Movie Legend, Table Legends 1-5 from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

Author

Littlepage, Laurie E., primary, Adler, Adam S., primary, Kouros-Mehr, Hosein, primary, Huang, Guiqing, primary, Chou, Jonathan, primary, Krig, Sheryl R., primary, Griffith, Obi L., primary, Korkola, James E., primary, Qu, Kun, primary, Lawson, Devon A., primary, Xue, Qing, primary, Sternlicht, Mark D., primary, Dijkgraaf, Gerrit J.P., primary, Yaswen, Paul, primary, Rugo, Hope S., primary, Sweeney, Colleen A., primary, Collins, Colin C., primary, Gray, Joe W., primary, Chang, Howard Y., primary, and Werb, Zena, primary

Published
2023
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13. Supplementary Movie from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression

Author

Littlepage, Laurie E., primary, Adler, Adam S., primary, Kouros-Mehr, Hosein, primary, Huang, Guiqing, primary, Chou, Jonathan, primary, Krig, Sheryl R., primary, Griffith, Obi L., primary, Korkola, James E., primary, Qu, Kun, primary, Lawson, Devon A., primary, Xue, Qing, primary, Sternlicht, Mark D., primary, Dijkgraaf, Gerrit J.P., primary, Yaswen, Paul, primary, Rugo, Hope S., primary, Sweeney, Colleen A., primary, Collins, Colin C., primary, Gray, Joe W., primary, Chang, Howard Y., primary, and Werb, Zena, primary

Published
2023
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26. Abstract IA022: Cell archetypes in human brain metastases: Connecting programs in tumor cells with the microenvironment

Author

Gonzalez, Hugo, primary, Mei, Wenbin, additional, Robles, Isabella, additional, Hagerling, Catharina, additional, Allen, Breanna, additional, Okholm, Trine Hauge, additional, Nanjaraj, Ankitha, additional, Verbeek, Tamara, additional, Kalavacherla, Sandhya, additional, Gogh, Merel van, additional, Georgiou, Stephen, additional, Daras, Mariza, additional, Phillips, Joanna J., additional, Spitzer, Matthew H., additional, Roose, Jeroen P., additional, and Werb, Zena, additional

Published
2023
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27. Dissecting the contributions of tumor heterogeneity on metastasis at single-cell resolution

Author

Winkler, Juliane, primary, Tan, Weilun, additional, Diadhiou, Catherine M. M., additional, McGinnis, Christopher S., additional, Abbasi, Aamna, additional, Hasnain, Saad, additional, Durney, Sophia, additional, Atamaniuc, Elena, additional, Superville, Daphne, additional, Awni, Leena, additional, Lee, Joyce V., additional, Hinrichs, Johanna H., additional, Hein, Marco Y., additional, Borja, Michael, additional, Detweiler, Angela, additional, Liu, Su-Yang, additional, Nanjaraj, Ankitha, additional, Sitarama, Vaishnavi, additional, Rugo, Hope S., additional, Neff, Norma, additional, Gartner, Zev J., additional, Pisco, Angela Oliveira, additional, Goga, Andrei, additional, Darmanis, Spyros, additional, and Werb, Zena, additional

Published
2022
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29. LGL1 binds to Integrin 01 and inhibits downstream signaling to promote epithelial branching in the mammary gland

Author

Ma, Rongze, Gong, Difei, You, Huanyang, Xu, Chongshen, Lu, Yunzhe, Bergers, Gabriele, Werb, Zena, Klein, Ophir D, Petritsch, Claudia K, and Liu, Pengfei

Subjects
tumor-suppressor genes, extracellular matrix, collective migration, branching morphogenesis, epithelial polarity, epithelial migration, integrin signaling
Abstract

Branching morphogenesis is a fundamental process by which organs in invertebrates and vertebrates form branches to expand their surface areas. The current dogma holds that directional cell migration determines where a new branch forms and thus patterns branching. Here, we asked whether mouse Lgl1, a homolog of the Drosophila tumor suppressor Lgl, regulates epithelial polarity in the mammary gland. Surprisingly, mammary glands lacking Lgl1 have normal epithelial polarity, but they form fewer branches. Moreover, we find that Lgl1 null epithelium is unable to directionally migrate, suggesting that migration is not essential for mammary epithelial branching as expected. We show that LGL1 binds to Integrin β1 and inhibits its downstream signaling, and Integrin β1 overexpression blocks epithelial migration, thus recapitulating the Lgl1 null phenotype. Altogether, we demonstrate that Lgl1 modulation of Integrin β1 signaling is essential for directional migration and that epithelial branching in invertebrates and the mammary gland is fundamentally distinct. ispartof: CELL REPORTS vol:38 issue:7 ispartof: location:United States status: published

Published
2022

30. A framework for advancing our understanding of cancer-associated fibroblasts

Author

Sahai, Erik, Astsaturov, Igor, Cukierman, Edna, DeNardo, David G., Egeblad, Mikala, Evans, Ronald M., Fearon, Douglas, Greten, Florian R., Hingorani, Sunil R., Hunter, Tony, Hynes, Richard O., Jain, Rakesh K., Janowitz, Tobias, Jorgensen, Claus, Kimmelman, Alec C., Kolonin, Mikhail G., Maki, Robert G., Powers, R. Scott, Puré, Ellen, Ramirez, Daniel C., Scherz-Shouval, Ruth, Sherman, Mara H., Stewart, Sheila, Tlsty, Thea D., Tuveson, David A., Watt, Fiona M., Weaver, Valerie, Weeraratna, Ashani T., Werb, Zena, Sahai, Erik, Astsaturov, Igor, Cukierman, Edna, DeNardo, David G., Egeblad, Mikala, Evans, Ronald M., Fearon, Douglas, Greten, Florian R., Hingorani, Sunil R., Hunter, Tony, Hynes, Richard O., Jain, Rakesh K., Janowitz, Tobias, Jorgensen, Claus, Kimmelman, Alec C., Kolonin, Mikhail G., Maki, Robert G., Powers, R. Scott, Puré, Ellen, Ramirez, Daniel C., Scherz-Shouval, Ruth, Sherman, Mara H., Stewart, Sheila, Tlsty, Thea D., Tuveson, David A., Watt, Fiona M., Weaver, Valerie, Weeraratna, Ashani T., and Werb, Zena

Abstract

© 2020, The Author(s). Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.

Published
2022

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