2020 conference-abstract

Abstract ES10-2: Understanding breast cancer using a developmental perspective

GM Wahl, Zhibo Ma, Chi‐Yeh Chung, Christopher Dravis, BT Spike, RT Giraddi, Ozlen Balcioglu, Cheng Fan, Berhane M. Hagos, Richard E. Heinz, Jaslem Herrera-Valdez, Xiaomeng Hou, Jae Yeon Hwang, Roger S. Lasken, Gidsela Luna, NE Lytle, EM Mehrabad, Mark A. Novotny, CM Perou, Olivier Poirion, Sebastian Preißl, Bin Ren, Tannishtha Reya, CL Trejo, K-T Varley

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Abstract Parallels among embryonic development, stem cells, and cancer have long been recognized. We identified, isolated, and characterized stem cells that first become committed to a mammary fate during embryogenesis; we refer to these cells as fetal mammary stem cells (fMaSCs). Lineage tracing, in vitro sphere formation, and in vivo transplantation studies by our group and many others all confirm that cells in the embryo are the bipotent progenitors of the mammary gland. There is debate, however, on whether such bipotent cells persist into the adult, or whether the luminal and basal lineages are maintained by unipotent progenitors. To gain insight into the relationships between fMaSCs and breast cancer, and to investigate their potential persistence in the adult, we have applied bulk and single cell RNA-sequencing (sc-RNA-seq) and single nucleus ATAC-sequencing (snATAC-seq) throughout mammary development. The results to be discussed demonstrate that fMaSC transcriptomes are heterogeneous, but all share co-expression of genes associated with luminal and basal cell fates. This fits a model in which the bipotent state is created by a balance of lineage specifiers. We also find that the fMaSC transcriptome is highly enriched in basal-like human breast cancers and identify potential embryonic pathways that correlate with poor prognosis. We used a variety of computational tools to infer the gene expression programs that ensue when fMaSCs commit to luminal and basal states. The data from scRNA-seq and snATAC-seq demonstrate that the transitions are gradual, not precipitous, and that luminal and basal cells exhibit significant transcriptomic and epigenetic heterogeneity. This challenges the notion that the mammary gland consists of discrete cell types defined by rigid transcriptomic parameters, and reveals a potential for intrinsic phenotypic plasticity of normal mammary cells. Using the combined databases, we identified Sox10 as a significantly differentially expressed cell state regulator. We show that tumors are heterogeneous with regard to Sox10 expression, and that locally invasive cells tend to express high Sox10 levels. Elevated Sox10 correlates with acquisition of a neural-crest like, EMT-related state. Implications for interception of metastasis by targeting neural crest-like cells will be discussed. Finally, we have generated a web resource that is available to the scientific community to enable the transcription and epigenetic characteristics of any gene of interest to be tracked through mammary development (https://wahl-labsalk.shinyapps.io/Mammary_snATAC/). Citation Format: GM Wahl, Z Ma, C Chung, C Dravis, BT Spike, RR Giraddi, O Balcioglu, C Fan, B Hagos, R Heinz, Herrera-Valdez J, X Hou, J Hwang, R Lasken, G Luna, NE Lytle, EM Mehrabad, M Novotny, CM Perou, O Poirion, S Preissl, B Ren, T Reya, CL Trejo, KT Varley. Understanding breast cancer using a developmental perspective [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES10-2.

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DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.

Titre Crossref: Abstract ES10-2: Understanding breast cancer using a developmental perspective
Date Crossref: 15/02/2020
Éditeur: American Association for Cancer Research (AACR)
Type: journal-article

Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.

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Salk Institute for Biological Studies pays non établi dans la notice
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Pfizer (United States) pays non établi dans la notice
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University of Utah Department of Oncological Sciences pays non établi dans la notice
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Huntsman Cancer Institute pays non établi dans la notice
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University of North Carolina at Chapel Hill pays non établi dans la notice
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University of California San Diego Department of Cellular and Molecular Medicine pays non établi dans la notice
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J. Craig Venter Institute pays non établi dans la notice
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Ludwig Cancer Research pays non établi dans la notice
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Sanford Consortium for Regenerative Medicine pays non établi dans la notice
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Gene Expression Laboratory pays non établi dans la notice
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La Jolla pays non établi dans la notice
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Ludwig Institute for Cancer Research pays non établi dans la notice
Structure de recherche

Salk Institute for Biological Studies, Pfizer (United States) et Department of Oncological Sciences — University of Utah, avec 9 autres affiliations.

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