The project has historically studied the action of tumor suppressor genes, and is based on the premise that tumor suppressors reveal key regulatory nodes in growth control processes and the strategies nature uses to combat cancer. Based on our observation that certain oncogenes promote apoptosis through p53, we initially explored the mechanisms by which p53 suppressed apoptosis and how disruption of p53 network components promoted tumorigenesis and impacted therapy response. Taking advantage of program collaborations, we later established how p53 loss sustains tumorigenesis and, by combining oncogenomics, functional genomics, and in vivo genetic screens, established the functional relevance of many cancer drivers. Over the last funding cycle, we expanded our efforts towards understanding how tumor suppressor loss is required for tumor maintenance, showing that re-establishing tumor suppressor networks can have profound and distinct anti- proliferative effects, even in advanced cancers. This evolution spawned our current interest in ?tumor maintenance genes? ? genes needed to sustain cancer progression ? and stimulated the development of new mouse models that enable suppression and/or reactivation of gene function at different stages of disease. Moving forward, the project will focus on the identification and characterization of tumor suppressor and tumor maintenance genes in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) ? two primary liver cancers for which genomic studies have identified few ?druggable? cancer drivers, and for which no effective therapies exist. As such, we now propose to characterize how mutations in certain chromatin-modifying genes ? which are common in human tumors but are poorly understood - drive tumor initiation and maintenance, and to implement new genetic and genomic tools to identify and validate therapeutic targets for primary liver cancers driven by these altered gene products. Our approach combines mouse models, genetic tools, and cancer genomics in a coordinated manner that enables the comprehensive interrogation of tumor suppressor and tumor maintenance network, and benefits from multiple interactions with other projects and cores. The project will produce a more complete understanding of how primary liver cancers are initiated and maintained while simultaneously validating new therapeutic targets for these diseases. As such, our project addresses an urgent and unmet clinical need.
This project explores the action of tumor suppressor and tumor maintenance genes in primarily liver cancers ? tumor types for which there is an unmet clinical need. It combines mouse models, genetic tools, and cancer genomics in a coordinated manner that enables the interrogation of tumor suppressor and tumor maintenance networks in a comprehensive way. We expect the proposed work to produce molecular insights into a new class of tumor suppressors that impact chromatin, and identify novel targets to exploit mutations in these genes.
|Li, Meng Amy; Amaral, Paulo P; Cheung, Priscilla et al. (2017) A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation. Elife 6:|
|Diermeier, Sarah D; Spector, David L (2017) Antisense Oligonucleotide-mediated Knockdown in Mammary Tumor Organoids. Bio Protoc 7:|
|Pelossof, Raphael; Fairchild, Lauren; Huang, Chun-Hao et al. (2017) Prediction of potent shRNAs with a sequential classification algorithm. Nat Biotechnol 35:350-353|
|Roe, Jae-Seok; Hwang, Chang-Il; Somerville, Tim D D et al. (2017) Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. Cell 170:875-888.e20|
|Zhang, Bin; Mao, Yuntao S; Diermeier, Sarah D et al. (2017) Identification and Characterization of a Class of MALAT1-like Genomic Loci. Cell Rep 19:1723-1738|
|Mu, Ping; Zhang, Zeda; Benelli, Matteo et al. (2017) SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355:84-88|
|Anczuków, Olga; Krainer, Adrian R (2016) Splicing-factor alterations in cancers. RNA 22:1285-301|
|Baker, Leena; BeGora, Michael; Au Yeung, Faith et al. (2016) Scribble is required for pregnancy-induced alveologenesis in the adult mammary gland. J Cell Sci 129:2307-15|
|Tasdemir, Nilgun; Banito, Ana; Roe, Jae-Seok et al. (2016) BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance. Cancer Discov 6:612-29|
|Hossain, Manzar; Stillman, Bruce (2016) Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription. Elife 5:|
Showing the most recent 10 out of 592 publications