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  • br evaluated as novel treatment strategies

    2019-10-14

    
    evaluated as novel treatment strategies for pancre-atic cancer patients.
    INTRODUCTION
    Although cytotoxic agents remain the standard of care for most cancers, their use is often associated with initial efÞcacy, fol-lowed by disease progression. This is particularly true for pancreatic cancer, a highly aggressive disease, where current multidrug chemotherapy regimens result in tumor regression in 30% of patients, quickly followed by disease progression in the vast majority of cases (Conroy et al., 2011). This progression is largely due to the inability of chemotherapy to successfully eradicate all tumor cells, leaving behind subpopulations that can trigger tumor re-growth. Thus, identifying the Methylpiperidino pyrazole that are preferentially drug resistant, and understanding their vulnerabil-ities, is critical to improving patient outcome and response to current therapies.
    In previous work, several groups have focused on identifying the most tumorigenic populations within pancreatic cancer. Through this, subpopulations of cells marked by expression of CD24+/CD44+/ESA+ (Li et al., 2007), cMet (Li et al., 2011), CD133 (Hermann et al., 2007), nestin (Kawamoto et al., 2009), ALDH (Rasheed et al., 2010), and more recently DCLK1 (Bailey et al., 2014) and Musashi (Fox et al., 2016), have been shown to harbor stem cell characteristics, in being enriched for the ca-pacity to drive tumorigenesis, and recreate the heterogeneity of
    the original tumor (Reya et al., 2001). Importantly, these tumor propagating cells or cancer stem cells have been shown to be highly resistant to cytotoxic therapies, such as gemcitabine, consistent with the Þnding that cancer patients with a high can-cer stem cell signature have poorer prognosis relative to those with a low stem cell signature (Grosse-Wilde et al., 2015). Although pancreatic cancer stem cells are epithelial in origin, these cells frequently express epithelial to mesenchymal transi-tion (EMT)-associated programs, which may in part explain their over-representation in circulation and propensity to seed meta-static sites (Fox et al., 2016; Hermann et al., 2007). Because these studies deÞne stem cells as a population that presents a particularly high risk for disease progression, deÞning the molec-ular signals that sustain them remains an essential goal for achieving complete and durable responses.
    Here, we have used a combination of RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR screening to deÞne the molecular framework that sustains the aggressive nature of pancreatic cancer stem cells. These studies identiÞed a network of key nodes regulating pancreatic cancer stem cells and revealed an unanticipated role for immuno-regulatory genes in their self-renewal and mainte-nance. Among these, the retinoic-acid-receptor-related orphan receptor gamma (RORg), a nuclear hormone receptor known for its role in Th17 cell speciÞcation and regulation of inßamma-tory cytokine production (Ivanov et al., 2006), emerged as a key regulator of stem cells. RORg expression increased with pro-gression, and its blockade via genetic or pharmacologic approaches depleted the cancer stem cell pool and profoundly inhibited human and mouse tumor propagation, in part by sup-pressing a super-enhancer-associated oncogenic network. Finally, sustained treatment with a RORg inhibitor led to a signif-icant improvement in autochthonous models of pancreatic can-cer. Together, our studies offer a unique comprehensive map of pancreatic cancer stem cells and identify critical vulnerabilities that may be exploited to improve therapeutic targeting of aggressive, drug-resistant pancreatic cancer cells.
    RESULTS
    Transcriptomic and Epigenetic Map of Pancreatic Cancer Cells Reveals a Unique Stem Cell State