Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Fátima Valdés-Mora¹, Robert Salomon², Brian Stewart Gloss³, Andrew Man Kit Law³, Jeron Venhuizen⁴, Lesley Castillo⁴, Kendelle Joan Murphy³, Astrid Magenau⁴, Michael Papanicolaou⁵, Laura Rodriguez de la Fuente⁶, Daniel Lee Roden⁷, Yolanda Colino-Sanguino⁸, Zoya Kikhtyak⁴, Nona Farbehi⁹, James Ronald William Conway⁴, Neblina Sikta¹⁰, Samantha Richelle Oakes³, Thomas Robert Cox³, Seán Ignatius O'Donoghue¹¹, Paul Timpson³, Christopher John Ormandy³, David Gallego-Ortega¹²

Affiliations

¹ Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. Electronic address: fvaldesmora@ccia.org.au.
² Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Institute for Biomedical Materials and Devices, University of Technology Sydney, Sydney, NSW 2007, Australia.
³ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁴ Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁵ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; School of Life Sciences, University of Technology Sydney, Sydney, NSW 2007, Australia.
⁶ Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁷ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁸ Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia.
⁹ Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
¹⁰ Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
¹¹ Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; CSIRO Data61, Eveleigh, NSW 2015, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2052, Australia.
¹² St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. Electronic address: d.gallego@garvan.org.au.

PMID: 33852842
DOI: 10.1016/j.celrep.2021.108945

Free article

Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Fátima Valdés-Mora et al. Cell Rep. 2021.

Free article

. 2021 Apr 13;35(2):108945.

doi: 10.1016/j.celrep.2021.108945.

Authors

Affiliations

¹ Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. Electronic address: fvaldesmora@ccia.org.au.
² Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Institute for Biomedical Materials and Devices, University of Technology Sydney, Sydney, NSW 2007, Australia.
³ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁴ Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁵ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; School of Life Sciences, University of Technology Sydney, Sydney, NSW 2007, Australia.
⁶ Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁷ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁸ Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia.
⁹ Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
¹⁰ Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
¹¹ Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; CSIRO Data61, Eveleigh, NSW 2015, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2052, Australia.
¹² St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. Electronic address: d.gallego@garvan.org.au.

PMID: 33852842
DOI: 10.1016/j.celrep.2021.108945

Abstract

Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.

Keywords: Elf5; alveolar lineage; basal breast cancer; cancer-associated fibroblast; involution; mammary gland epithelial hierarchy; pregnancy-associated breast cancer; scRNA-seq.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Affiliations

Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases