Seminar: Deconstructing Breast Cancer Using a Developmental Perspective

Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity. Cancer Cell, 34(3):466-482.

Christopher Dravis1, Chi-Yeh Chung2, Nikki K Lytle3, Jaslem Herrera-Valdez2, Gidsela Luna2, Christy L Trejo2, Tannishtha Reya3, Geoffrey M Wahl4

  1. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: cdravis@salk.edu.
  2. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  3. Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Departments of Pharmacology and Medicine, Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92037, USA.
  4. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: wahl@salk.edu.

Abstract

Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during mammary development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells. In both mouse and human tumors, SOX10 expression correlates with stem/progenitor identity, dedifferentiation, and invasive characteristics. Strikingly, we demonstrate that SOX10 binds to genes that regulate neural crest cell identity, and that SOX10-positive tumor cells exhibit neural crest cell features.

Single cell transcriptomes distinguish stem cell state changes and lineage specification programs in early mammary gland development. Cell Reports. 24(6):1653-1666.

Rajshekhar R Giraddi1, Chi-Yeh Chung1, Richard E Heinz2, Ozlen Balcioglu2, Mark Novotny3, Christy L Trejo1, Christopher Dravis1, Berhane M Hagos2, Elnaz Mirzaei Mehrabad2, Luo Wei Rodewald1, Jae Y Hwang2, Cheng Fan4, Roger Lasken3, Katherine E Varley2, Charles M Perou4, Geoffrey M Wahl5, Benjamin T Spike6

  1. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  2. Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
  3. J. Craig Venter Institute, La Jolla, CA 92037, USA.
  4. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  5. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: wahl@salk.edu.
  6. Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: benjamin.spike@hci.utah.edu.

Abstract

The mammary gland consists of cells with gene expression patterns reflecting their cellular origins, function, and spatiotemporal context. However, knowledge of developmental kinetics and mechanisms of lineage specification is lacking. We address this significant knowledge gap by generating a single-cell transcriptome atlas encompassing embryonic, postnatal, and adult mouse mammary development. From these data, we map the chronology of transcriptionally and epigenetically distinct cell states and distinguish fetal mammary stem cells (fMaSCs) from their precursors and progeny. fMaSCs show balanced co-expression of factors associated with discrete adult lineages and a metabolic gene signature that subsides during maturation but reemerges in some human breast cancers and metastases. These data provide a useful resource for illuminating mammary cell heterogeneity, the kinetics of differentiation, and developmental correlates of tumorigenesis.

Single-cell chromatin accessibility analysis of mammary gland development reveals cell state transcriptional regulators and cellular lineage relationships. Cell Reports. 29(2):495-510.

Chi-Yeh Chung1, Zhibo Ma1, Christopher Dravis1, Sebastian Preissl2, Olivier Poirion2, Gidsela Luna1, Xiaomeng Hou2, Rajshekhar R Giraddi1, Bing Ren3, Geoffrey M Wahl4

  1. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  2. Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
  3. Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
  4. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: wahl@salk.edu.

Abstract

Technological improvements enable single-cell epigenetic analyses of organ development. We reasoned that high-resolution single-cell chromatin accessibility mapping would provide needed insight into the epigenetic reprogramming and transcriptional regulators involved in normal mammary gland development. Here, we provide a single-cell resource of chromatin accessibility for murine mammary development from the peak of fetal mammary stem cell (fMaSC) functional activity in late embryogenesis to the differentiation of adult basal and luminal cells. We find that the chromatin landscape within individual cells predicts both gene accessibility and transcription factor activity. The ability of single-cell chromatin profiling to separate E18 fetal mammary cells into clusters exhibiting basal-like and luminal-like chromatin features is noteworthy. Such distinctions were not evident in analyses of droplet-based single-cell transcriptomic data. We present a web application as a scientific resource for facilitating future analyses of the gene regulatory networks involved in mammary development.

Presented By Geoffrey Wahl

Cancer Biology, SeminarsNicholas Liao2019-10 (Oct)