Transcriptomic Subtypes of Pancreatic Ductal Adenocarcinoma Share Patterns of Dysregulated Gene Expression and Survival Dependencies
Derek Crowe • Land Lab, University of Rochester • January 2023
Tumor recurrence is an extremely common and deadly response to therapy observed across human malignancies. The dismal outlook for patients diagnosed with Pancreatic Ductal Adenocarcinoma (PDAC) can be attributed largely to the ability of tumor cells to survive both standard and targeted therapies, highlighting the profound need to understand how tumor cells respond to and survive therapy. Transcriptomic studies of human PDAC tumors have revealed molecular subtypes among primary and recurrent cells with prognostic and biological relevance.
Descriptions of differences that underlie subtype biology are critical if the field is to identify and target vulnerabilities they may possess, but the phenotypic heterogeneity and plasticity displayed by PDAC tumor subtypes suggest that targeting those vulnerabilities may be insufficient. Shared hallmark properties are displayed by all tumors and subtypes, many of which are mediated by the dysregulated expression of non-mutated genes acting downstream of transforming oncogenic lesions. We hypothesized that common patterns of transcriptomic dysregulation could be identified among the distinct subtypes of PDAC and that the identity of genes participating in dysregulated programming could point to shared mechanisms supporting their survival.
We modeled a targeted therapy by ablating oncogenic expression in primary PDAC tumors and observed the outgrowth of recurrences. These matched primary and recurrent tumors recapitulated multiple aspects of PDAC biology observed in human patients, including the distribution of molecular subtypes. Independent component analysis identified patterns of transcriptomic dysregulation shared by distinct PDAC phenotypes, and an in vivo pooled loss of function CRISPR screen revealed a set of genes that mediate survival mechanisms across subtypes of primary and recurrent tumor cells. We conclude that molecularly-distinct tumors harbor common genetic dependencies. Such shared dependencies serve to reframe the way we approach the identification of potential therapeutically-relevant vulnerabilities and widen our lens to consider genetic mechanisms that promote survival in multiple contexts of tumor biology.
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