Project description:Therapy resistance and resultant relapse remain key challenges in pancreatic cancer, and are in part driven by the inherent heterogeneity of the tumor that prevents effective targeting of all malignant cells. Here we utilized a combination of RNA-seq, ChIP-seq and genome-wide CRISPR screening to systematically map the dependencies of pancreatic cancer stem cells, highly drug resistant cells that are also enriched in the capacity to drive progression 1-4 . Integration of these data revealed an unexpected role for immuno-regulatory genes in stem cell self-renewal and maintenance in KP f/f C tumors. In particular, Retinoic acid receptor-related orphan receptor gamma (ROR g) , a nuclear hormone receptor known for its role in inflammatory cytokine responses and T cell differentiation 5,6 , emerged as a key regulator of stem cells. ROR g expression rose with pancreatic cancer progression, and its inhibition via genetic approaches or small molecule inhibitors led to a striking defect in pancreatic cancer growth in vitro and in vivo. Collectively, these data reveal an unexpected co-option of immuno-regulatory signals by pancreatic cancer stem cells, and suggest that therapeutics currently being used for autoimmune indications should be considered for treatment of pancreatic cancer.
Project description:Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (ROR?), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that ROR? expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.
Project description:Pancreatic adenocarcinoma is one of the most aggressive human cancers and displays many different chromosomal abnormalities and mutations. By using 244K high-resolution array-comparative genomic hybridization (aCGH) we studied the genome alterations of 39 fine-needle aspirations from pancreatic adenocarcinoma and 9 human adenocarcinoma pancreatic cell lines.
Project description:To further develop our understanding of the gene expression signature of pancreatic ductal adenocarcinoma Gene expression signatures in macrodissected resected pancreatic ductal adenocarcinoma specimens
Project description:We sought to determine whether certain miRNAs could serve as a biomarker for the prognosis of pancreatic ductal adenocarcinoma (PDAC) and uncover the uncharacterized miRNAs function in the pancreatic carcinogenesis
Project description:RNA-seq profiling was conducted on clinically-annotated human pancreatic adenocarcinoma cancer tissues We measured the transcriptome in 51 clinically-annotated human pancreatic adenocarcinoma cancer tissues