Regulation of cellular differentiation is critical for tissue homeostasis and its disruption underlies many disease processes including cancer. Our objective is to understand the cellular and genetic mechanisms that direct the self-renewal and differentiation of stem cells in normal tissues and in cancer. To this end, we apply an inter-disciplinary approach involving massively parallel RNAi screening, computational modeling, chemical genetics, gene-expression profiling, next-generation sequencing and in vivo models.
Identification of genes that regulate stem and progenitor cell biology
We examine the development of mammary gland as a system in which to study adult stem cell biology. The mammary epithelium undergoes regenerative proliferation, terminal differentiation and regression during each cycle of pregnancy and lactation. The mouse mammary gland is well-suited for studies of tissue development and stem cells since the epithelial portion of the gland can be cleared and reconstituted via transplantation. We are using RNAi screens and chromatin-mapping, together with in vivo modeling, to identify genes that are required for mammary stem cell specification and maintenance.
Molecular probes of cancer stem cell biology
We have developed a novel screening strategy to identify small molecules that exhibit selective lethality towards cancer cells in a stem-like state. Using this approach, we have discovered small molecules that are selectively toxic towards cancer stem cells. We are using these chemical probes together with RNAi screening to uncover signaling pathways that are important for cancer stem cell maintenance and function.
Quantitative models of cell-state dynamics
Given the randomness inherent in molecular processes, it is unclear how normal and cancerous tissues maintain phenotypic equilibrium. We are developing quantitative models to better understand how stochasticity at the single-cell level contributes to phenotypic stability in cellular populations. We are combining computational models with RNAi screening data to build more comprehensive models of state transitions in cellular populations.
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Piyush B. Gupta, Christine Chaffer, Robert A. Weinberg. “Cancer stem cells: mirage or reality?” Nature Medicine. (2009) Sep; 15(9):1010-1012.
Piyush B. Gupta, Tamer T. Onder, Guozhi Jiang, Kai Tao, Charlotte Kuperwasser, Robert A. Weinberg, Eric S. Lander. “Identification of selective inhibitors of cancer stem cells by high-throughput screening.” Cell. (2009) Aug; 138(4):645-659.
Piyush B. Gupta, Sendurai Mani, Jing Yang, Kimberly Hartwell, Robert A. Weinberg. “The evolving portrait of cancer metastasis.” Cold Spring Harbor Symposia on Quantitative Biology. (2005) 70: 291-298.
Piyush B. Gupta, Charlotte Kuperwasser, Jean-Philippe Brunet, Sridhar Ramaswamy, Wen-Lin Kuo, Joe W. Gray, Stephen P. Naber, Robert A. Weinberg. “The melanocyte differentiation program predisposes to metastasis after neoplastic transformation.” Nature Genetics. (2005) Oct; 37(10):1047-54.
Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA. “Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.” Cell. (2005) May 6; 121(3):335-48.