Skip to main content
Top
Published in: Journal of Mammary Gland Biology and Neoplasia 1/2024

Open Access 01-12-2024 | Estrogens | Research

Single-Cell Transcription Mapping of Murine and Human Mammary Organoids Responses to Female Hormones

Authors: Jenelys Ruiz Ortiz, Steven M. Lewis, Michael Ciccone, Deeptiman Chatterjee, Samantha Henry, Adam Siepel, Camila O. dos Santos

Published in: Journal of Mammary Gland Biology and Neoplasia | Issue 1/2024

Login to get access

Abstract

During female adolescence and pregnancy, rising levels of hormones result in a cyclic source of signals that control the development of mammary tissue. While such alterations are well understood from a whole-gland perspective, the alterations that such hormones bring to organoid cultures derived from mammary glands have yet to be fully mapped. This is of special importance given that organoids are considered suitable systems to understand cross species breast development. Here we utilized single-cell transcriptional profiling to delineate responses of murine and human normal breast organoid systems to female hormones across evolutionary distinct species. Collectively, our study represents a molecular atlas of epithelial dynamics in response to estrogen and pregnancy hormones.
Appendix
Available only for authorised users
Literature
1.
go back to reference Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, Rambow F, Marine J-C, Geurts P, Aerts J, van den Oord J, Atak ZK, Wouters J, Aerts S. SCENIC: Single-cell regulatory network inference and clustering. Nat Methods. 2017;14(11):11. https://doi.org/10.1038/nmeth.4463.CrossRef Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, Rambow F, Marine J-C, Geurts P, Aerts J, van den Oord J, Atak ZK, Wouters J, Aerts S. SCENIC: Single-cell regulatory network inference and clustering. Nat Methods. 2017;14(11):11. https://​doi.​org/​10.​1038/​nmeth.​4463.CrossRef
3.
go back to reference Asselin-Labat M-L, Sutherland KD, Vaillant F, Gyorki DE, Wu D, Holroyd S, Breslin K, Ward T, Shi W, Bath ML, Deb S, Fox SB, Smyth GK, Lindeman GJ, Visvader JE. Gata-3 negatively regulates the tumor-initiating capacity of mammary luminal progenitor cells and targets the putative tumor suppressor caspase-14. Mol Cell Biol. 2011;31(22):4609–22. https://doi.org/10.1128/MCB.05766-11.CrossRefPubMedPubMedCentral Asselin-Labat M-L, Sutherland KD, Vaillant F, Gyorki DE, Wu D, Holroyd S, Breslin K, Ward T, Shi W, Bath ML, Deb S, Fox SB, Smyth GK, Lindeman GJ, Visvader JE. Gata-3 negatively regulates the tumor-initiating capacity of mammary luminal progenitor cells and targets the putative tumor suppressor caspase-14. Mol Cell Biol. 2011;31(22):4609–22. https://​doi.​org/​10.​1128/​MCB.​05766-11.CrossRefPubMedPubMedCentral
9.
go back to reference Bhatia S, Kramer M, Russo S, Naik P, Arun G, Brophy K, Andrews P, Fan C, Perou CM, Preall J, Ha T, Plenker D, Tuveson DA, Rishi A, Wilkinson JE, McCombie WR, Kostroff K, Spector DL. Patient-derived triple-negative breast cancer organoids provide robust model systems that recapitulate tumor intrinsic characteristics. Can Res. 2022;82(7):1174–92. https://doi.org/10.1158/0008-5472.CAN-21-2807.CrossRef Bhatia S, Kramer M, Russo S, Naik P, Arun G, Brophy K, Andrews P, Fan C, Perou CM, Preall J, Ha T, Plenker D, Tuveson DA, Rishi A, Wilkinson JE, McCombie WR, Kostroff K, Spector DL. Patient-derived triple-negative breast cancer organoids provide robust model systems that recapitulate tumor intrinsic characteristics. Can Res. 2022;82(7):1174–92. https://​doi.​org/​10.​1158/​0008-5472.​CAN-21-2807.CrossRef
12.
go back to reference Bolado-Carrancio A, Lee M, Ewing A, Muir M, Macleod KG, Gallagher WM, Nguyen LK, Carragher NO, Semple CA, Brunton VG, Caswell PT, von Kriegsheim A. ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling. Oncogene. 2021;40(44):44. https://doi.org/10.1038/s41388-021-02017-8.CrossRef Bolado-Carrancio A, Lee M, Ewing A, Muir M, Macleod KG, Gallagher WM, Nguyen LK, Carragher NO, Semple CA, Brunton VG, Caswell PT, von Kriegsheim A. ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling. Oncogene. 2021;40(44):44. https://​doi.​org/​10.​1038/​s41388-021-02017-8.CrossRef
32.
go back to reference Fu NY, Rios AC, Pal B, Law CW, Jamieson P, Liu R, Vaillant F, Jackling F, Liu KH, Smyth GK, Lindeman GJ, Ritchie ME, Visvader JE. Identification of quiescent and spatially restricted mammary stem cells that are hormone responsive. Nat Cell Biol. 2017;19(3):3. https://doi.org/10.1038/ncb3471.CrossRef Fu NY, Rios AC, Pal B, Law CW, Jamieson P, Liu R, Vaillant F, Jackling F, Liu KH, Smyth GK, Lindeman GJ, Ritchie ME, Visvader JE. Identification of quiescent and spatially restricted mammary stem cells that are hormone responsive. Nat Cell Biol. 2017;19(3):3. https://​doi.​org/​10.​1038/​ncb3471.CrossRef
33.
go back to reference Gallego MI, Binart N, Robinson GW, Okagaki R, Coschigano KT, Perry J, Kopchick JJ, Oka T, Kelly PA, Hennighausen L. Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects. Dev Biol. 2001;229(1):163–75. https://doi.org/10.1006/dbio.2000.9961.CrossRefPubMed Gallego MI, Binart N, Robinson GW, Okagaki R, Coschigano KT, Perry J, Kopchick JJ, Oka T, Kelly PA, Hennighausen L. Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects. Dev Biol. 2001;229(1):163–75. https://​doi.​org/​10.​1006/​dbio.​2000.​9961.CrossRefPubMed
37.
go back to reference Guillen KP, Fujita M, Butterfield AJ, Scherer SD, Bailey MH, Chu Z, DeRose YS, Zhao L, Cortes-Sanchez E, Yang C-H, Toner J, Wang G, Qiao Y, Huang X, Greenland JA, Vahrenkamp JM, Lum DH, Factor RE, Nelson EW, Welm AL. A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology. Nat Cancer. 2022;3(2):2. https://doi.org/10.1038/s43018-022-00337-6.CrossRef Guillen KP, Fujita M, Butterfield AJ, Scherer SD, Bailey MH, Chu Z, DeRose YS, Zhao L, Cortes-Sanchez E, Yang C-H, Toner J, Wang G, Qiao Y, Huang X, Greenland JA, Vahrenkamp JM, Lum DH, Factor RE, Nelson EW, Welm AL. A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology. Nat Cancer. 2022;3(2):2. https://​doi.​org/​10.​1038/​s43018-022-00337-6.CrossRef
53.
go back to reference Ketterer S, Mitschke J, Ketscher A, Schlimpert M, Reichardt W, Baeuerle N, Hess ME, Metzger P, Boerries M, Peters C, Kammerer B, Brummer T, Steinberg F, Reinheckel T. Cathepsin D deficiency in mammary epithelium transiently stalls breast cancer by interference with mTORC1 signaling. Nat Commun. 2020;11(1):1. https://doi.org/10.1038/s41467-020-18935-2.CrossRef Ketterer S, Mitschke J, Ketscher A, Schlimpert M, Reichardt W, Baeuerle N, Hess ME, Metzger P, Boerries M, Peters C, Kammerer B, Brummer T, Steinberg F, Reinheckel T. Cathepsin D deficiency in mammary epithelium transiently stalls breast cancer by interference with mTORC1 signaling. Nat Commun. 2020;11(1):1. https://​doi.​org/​10.​1038/​s41467-020-18935-2.CrossRef
54.
go back to reference Klinke DJ, Torang A. An unsupervised feature extraction and selection strategy for identifying epithelial-mesenchymal transition state metrics in breast cancer and melanoma [Preprint]. Cancer Biol. 2019. https://doi.org/10.1101/865139. Klinke DJ, Torang A. An unsupervised feature extraction and selection strategy for identifying epithelial-mesenchymal transition state metrics in breast cancer and melanoma [Preprint]. Cancer Biol. 2019. https://​doi.​org/​10.​1101/​865139.
55.
go back to reference Koledova Z, Lu P. (2017). A 3D Fibroblast-Epithelium Co-culture Model for Understanding Microenvironmental Role in Branching Morphogenesis of the Mammary Gland. In F. Martin, T. Stein, & J. Howlin (Eds.), Mammary Gland Development: Methods and Protocols (pp. 217–231). Springer. https://doi.org/10.1007/978-1-4939-6475-8_10. Koledova Z, Lu P. (2017). A 3D Fibroblast-Epithelium Co-culture Model for Understanding Microenvironmental Role in Branching Morphogenesis of the Mammary Gland. In F. Martin, T. Stein, & J. Howlin (Eds.), Mammary Gland Development: Methods and Protocols (pp. 217–231). Springer. https://​doi.​org/​10.​1007/​978-1-4939-6475-8_​10.
60.
go back to reference Li C-W, Xia W, Huo L, Lim S-O, Wu Y, Hsu JL, Chao C-H, Yamaguchi H, Yang N-K, Ding Q, Wang Y, Lai Y-J, LaBaff AM, Wu T-J, Lin B-R, Yang M-H, Hortobagyi GN, Hung M-C. Epithelial-mesenchymal transition induced by TNF-α requires NF-κB–mediated transcriptional upregulation of twist1. Can Res. 2012;72(5):1290–300. https://doi.org/10.1158/0008-5472.CAN-11-3123.CrossRef Li C-W, Xia W, Huo L, Lim S-O, Wu Y, Hsu JL, Chao C-H, Yamaguchi H, Yang N-K, Ding Q, Wang Y, Lai Y-J, LaBaff AM, Wu T-J, Lin B-R, Yang M-H, Hortobagyi GN, Hung M-C. Epithelial-mesenchymal transition induced by TNF-α requires NF-κB–mediated transcriptional upregulation of twist1. Can Res. 2012;72(5):1290–300. https://​doi.​org/​10.​1158/​0008-5472.​CAN-11-3123.CrossRef
61.
go back to reference Li W, Zhang Z, Liu X, Cheng X, Zhang Y, Han X, Zhang Y, Liu S, Yang J, Xu B, He L, Sun L, Liang J, Shang Y. (n.d.). The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer. J Clin Investig. 127(9):3421–3440. https://doi.org/10.1172/JCI94233 Li W, Zhang Z, Liu X, Cheng X, Zhang Y, Han X, Zhang Y, Liu S, Yang J, Xu B, He L, Sun L, Liang J, Shang Y. (n.d.). The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer. J Clin Investig. 127(9):3421–3440. https://​doi.​org/​10.​1172/​JCI94233
74.
77.
go back to reference Mootha VK, Lindgren CM, Eriksson K-F, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Groop LC. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34(3):3. https://doi.org/10.1038/ng1180.CrossRef Mootha VK, Lindgren CM, Eriksson K-F, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Groop LC. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34(3):3. https://​doi.​org/​10.​1038/​ng1180.CrossRef
82.
go back to reference Nguyen-Ngoc, K.-V., Shamir, E. R., Huebner, R. J., Beck, J. N., Cheung, K. J., & Ewald, A. J. (2015). 3D Culture Assays of Murine Mammary Branching Morphogenesis and Epithelial Invasion. In C. M. Nelson (Ed.), Tissue Morphogenesis: Methods and Protocols (pp. 135–162). Springer. https://doi.org/10.1007/978-1-4939-1164-6_10. Nguyen-Ngoc, K.-V., Shamir, E. R., Huebner, R. J., Beck, J. N., Cheung, K. J., & Ewald, A. J. (2015). 3D Culture Assays of Murine Mammary Branching Morphogenesis and Epithelial Invasion. In C. M. Nelson (Ed.), Tissue Morphogenesis: Methods and Protocols (pp. 135–162). Springer. https://​doi.​org/​10.​1007/​978-1-4939-1164-6_​10.
88.
go back to reference Pal B, Chen Y, Vaillant F, Jamieson P, Gordon L, Rios AC, Wilcox S, Fu N, Liu KH, Jackling FC, Davis MJ, Lindeman GJ, Smyth GK, Visvader JE. Construction of developmental lineage relationships in the mouse mammary gland by single-cell RNA profiling. Nat Commun. 2017;8(1):1. https://doi.org/10.1038/s41467-017-01560-x.CrossRef Pal B, Chen Y, Vaillant F, Jamieson P, Gordon L, Rios AC, Wilcox S, Fu N, Liu KH, Jackling FC, Davis MJ, Lindeman GJ, Smyth GK, Visvader JE. Construction of developmental lineage relationships in the mouse mammary gland by single-cell RNA profiling. Nat Commun. 2017;8(1):1. https://​doi.​org/​10.​1038/​s41467-017-01560-x.CrossRef
90.
go back to reference Phipson B, Sim CB, Porrello ER, Hewitt AW, Powell J, Oshlack A. propeller: testing for differences in cell type proportions in single cell data. Bioinformatics. 2022;38(20):4720–6.CrossRefPubMedPubMedCentral Phipson B, Sim CB, Porrello ER, Hewitt AW, Powell J, Oshlack A. propeller: testing for differences in cell type proportions in single cell data. Bioinformatics. 2022;38(20):4720–6.CrossRefPubMedPubMedCentral
91.
go back to reference Poli V, Fagnocchi L, Fasciani A, Cherubini A, Mazzoleni S, Ferrillo S, Miluzio A, Gaudioso G, Vaira V, Turdo A, Gaggianesi M, Chinnici A, Lipari E, Bicciato S, Bosari S, Todaro M, Zippo A. MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state. Nat Commun. 2018;9(1):1. https://doi.org/10.1038/s41467-018-03264-2.CrossRef Poli V, Fagnocchi L, Fasciani A, Cherubini A, Mazzoleni S, Ferrillo S, Miluzio A, Gaudioso G, Vaira V, Turdo A, Gaggianesi M, Chinnici A, Lipari E, Bicciato S, Bosari S, Todaro M, Zippo A. MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state. Nat Commun. 2018;9(1):1. https://​doi.​org/​10.​1038/​s41467-018-03264-2.CrossRef
99.
go back to reference Rubio MF, Werbajh S, Cafferata EGA, Quaglino A, Coló GP, Nojek IM, Kordon EC, Nahmod VE, Costas MA. TNF-α enhances estrogen-induced cell proliferation of estrogen-dependent breast tumor cells through a complex containing nuclear factor-kappa B. Oncogene. 2006;25(9):9. https://doi.org/10.1038/sj.onc.1209176.CrossRef Rubio MF, Werbajh S, Cafferata EGA, Quaglino A, Coló GP, Nojek IM, Kordon EC, Nahmod VE, Costas MA. TNF-α enhances estrogen-induced cell proliferation of estrogen-dependent breast tumor cells through a complex containing nuclear factor-kappa B. Oncogene. 2006;25(9):9. https://​doi.​org/​10.​1038/​sj.​onc.​1209176.CrossRef
102.
go back to reference Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, Balgobind AV, Wind K, Gracanin A, Begthel H, Korving J, van Boxtel R, Duarte AA, Lelieveld D, van Hoeck A, Ernst RF, Blokzijl F, Nijman IJ, Hoogstraat M, … Clevers H. A living biobank of breast cancer organoids captures disease heterogeneity. Cell. 2018;172(1):373–386.e10. https://doi.org/10.1016/j.cell.2017.11.010 Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, Balgobind AV, Wind K, Gracanin A, Begthel H, Korving J, van Boxtel R, Duarte AA, Lelieveld D, van Hoeck A, Ernst RF, Blokzijl F, Nijman IJ, Hoogstraat M, … Clevers H. A living biobank of breast cancer organoids captures disease heterogeneity. Cell. 2018;172(1):373–386.e10. https://​doi.​org/​10.​1016/​j.​cell.​2017.​11.​010
121.
139.
Metadata
Title
Single-Cell Transcription Mapping of Murine and Human Mammary Organoids Responses to Female Hormones
Authors
Jenelys Ruiz Ortiz
Steven M. Lewis
Michael Ciccone
Deeptiman Chatterjee
Samantha Henry
Adam Siepel
Camila O. dos Santos
Publication date
01-12-2024
Publisher
Springer US
Keyword
Estrogens
Published in
Journal of Mammary Gland Biology and Neoplasia / Issue 1/2024
Print ISSN: 1083-3021
Electronic ISSN: 1573-7039
DOI
https://doi.org/10.1007/s10911-023-09553-x

Other articles of this Issue 1/2024

Journal of Mammary Gland Biology and Neoplasia 1/2024 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine