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Cejas, Paloma

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Cejas

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Paloma

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Cejas, Paloma

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2015 - 20192

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Author's Publications: search.filters.isAuthorOfPublication.f8c82b88-fc9c-474e-a426-7af47a48a541

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    The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis
    (2015) Pomerantz, Mark; Li, Fugen; Takeda, David; Lenci, Romina; Chonkar, Apurva; Chabot, Matthew; Cejas, Paloma; Vazquez, Francisca; Cook, Jennifer; Shivdasani, Ramesh; Bowden, Michaela; Lis, Rosina; Hahn, William; Kantoff, Philip; Brown, Myles; Loda, Massimo; Long, Henry; Freedman, Matthew
    Master transcription factors interact with DNA to establish cell-type identity and to regulate gene expression in mammalian cells1,2. The genome-wide map of these transcription factor binding sites has been termed the cistrome3. Here we show that the androgen receptor (AR) cistrome undergoes extensive reprogramming during prostate epithelial transformation in man. Using human prostate tissue, we observed a core set of AR binding sites that are consistently reprogrammed in tumors. FOXA1 and HOXB13, co-localized with the reprogrammed AR sites in human tumor tissue. Introduction of FOXA1 and HOXB13 into an immortalized prostate cell line reprogrammed the AR cistrome to resemble that of a prostate tumor, functionally linking these specific factors to AR reprogramming. These findings offer mechanistic insights into a key set of events that drive normal prostate epithelium towards transformation and establish the centrality of epigenetic reprogramming in human prostate tumorigenesis.
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    Enhancer Signatures Stratify and Predict Outcomes of Non-Functional Pancreatic Neuroendocrine Tumors
    (Springer Science and Business Media LLC, 2019-07-01) Cejas, Paloma; Drier, Yotam; Brosens, Lodewijk A. A.; Deshpande, Vikram; Morsink, Folkert H. M.; Graham, Mindy K.; Valk, Gerlof D.; Vriens, Menno R.; Fernandez-Del Castillo, Carlos; Fabiana Lucia da Silva, Annacarolina; Font-Tello, Alba; Heaphy, Christopher M.; Sicinska, Ewa; Dreijerink, Koen; Epstein, Charles; Conemans, Elfi; Ferrone, Cristina; Adar, Tomer; Bowden, Michaela; Whitton, Holly; Long, Henry; Gaskell, Elizabeth; Shoresh, Noam; Kulke, Matthew; Chung, Daniel; Bernstein, Bradley; Shivdasani, Ramesh
    Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’. As clinical behaviors vary widely and distant metastases are eventually lethal, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major sub-types whose epigenomes and transcriptomes partially resemble islet alpha and beta cells. Transcription factors ARX and PDX1 specify these normal cells, respectively, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1- tumors and, within this sub-type, in cases with alternative lengthening of telomeres (ALT). These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course, and can inform post-operative clinical decisions.