While virtually all human tumors are derived from a single cell-of-origin, neoplastic cells within a tumor evolve over time due to genetic and epigenetic alterations, lineage diversification, and influences from stromal cells. These processes generate considerable heterogeneity within populations of neoplastic cells from individual tumors. Despite our knowledge of the existence of tumor cell heterogeneity, it is not understood whether the heterogeneous subpopulations of tumor cells merely co-exist, or alternatively whether they communicate with each other, complementing one another's phenotypes and generating biological outcomes that individual populations are incapable of producing on their own. The lack of understanding of such functional interactions between tum9r populations has been due in large part to the inability to maintain the heterogeneity of human tumors in culture and to propagate distinct clonal subpopulations from individual tumors. We and our collaborators have developed approaches that have overcome these barriers and made it feasible to culture bar-coded, fluorescently-tagged, clonal populations of tumor cells and then track individual clonal populations within tumor xenografts generated from mixtures of transplanted clones. Using these approaches, we have obtained evidence the supports the hypothesis that clonal subpopulations within a tumor cooperate with one another to promote tumor expansion and metastasis. In this proposal, we describe plans to test this hypothesis in human breast tumors by (1) characterizing the extent of genetic and phenotypic variation among clonal populations derived from an individual breast tumor and analyzing the tumor-initiating, invasive, and metastatic activity of each clonal subpopulation, (2) generating a map that plots the localization of clonal populations within tumors and their dynamic evolution over time, (3) investigating the functional consequences of heterogeneity within human breast tumor cell populations, and (4) elucidating the mechanisms responsible for phenotypes generated by intratumoral crosstalk. These studies will provide important insights into the nature of cooperative interactions between tumor cell populations and how these affect tumor expansion, invasion, or metastasis.

Public Health Relevance

The proposed studies on heterogeneity of neoplastic cells from human breast tumors will not only reveal important new information on the functional significance of intratumoral heterogeneity that is critical for understanding the evolution and dynamics of tumor cell development, progression and metastasis, but the findings will also be highly relevant to issues related to diagnosis, treatment efficacy, and identification of drug targets.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Whitehead Institute for Biomedical Research
United States
Zip Code
Witwicki, Robert M; Ekram, Muhammad B; Qiu, Xintao et al. (2018) TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer. Cell Rep 25:1255-1267.e5
Jeselsohn, Rinath; Bergholz, Johann S; Pun, Matthew et al. (2018) Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations. Cancer Cell 33:173-186.e5
Hinohara, Kunihiko; Wu, Hua-Jun; Vigneau, S├ębastien et al. (2018) KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. Cancer Cell 34:939-953.e9
Wan, Lixin; Xu, Kexin; Wei, Yongkun et al. (2018) Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function. Mol Cell 69:279-291.e5
Xiao, Tengfei; Li, Wei; Wang, Xiaoqing et al. (2018) Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy. Proc Natl Acad Sci U S A 115:7869-7878
Zhang, Jinfang; Bu, Xia; Wang, Haizhen et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91-95
Li, Andrew G; Murphy, Elizabeth C; Culhane, Aedin C et al. (2018) BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1? activation. Proc Natl Acad Sci U S A 115:E9600-E9609
Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro E et al. (2018) Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2-ER?-GREB1 Transcriptional Axis. Cancer Res 78:671-684
Dreijerink, Koen M A; Timmers, H T Marc; Brown, Myles (2017) Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. Endocr Relat Cancer 24:T135-T145
Rashidian, Mohammad; Ingram, Jessica R; Dougan, Michael et al. (2017) Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med 214:2243-2255

Showing the most recent 10 out of 136 publications