| First Author | Lytle NK | Year | 2019 |
| Journal | Cell | Volume | 177 |
| Issue | 3 | Pages | 572-586.e22 |
| PubMed ID | 30955884 | Mgi Jnum | J:283863 |
| Mgi Id | MGI:6389835 | Doi | 10.1016/j.cell.2019.03.010 |
| Citation | Lytle NK, et al. (2019) A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma. Cell 177(3):572-586.e22 |
| abstractText | 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 (RORgamma), 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 RORgamma 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. |
