Transcriptomic Subtypes of Pancreatic Ductal Adenocarcinoma Share Patterns of Dysregulated Gene Expression and Survival Dependencies
Derek Crowe • Land Lab, University of Rochester • January 2023
What does that mean? Pancreatic cancer is one of the most deadly cancers because it often returns after treatment and is very difficult to cure. Scientists know that not all pancreatic cancers are the same—there are different types within each tumor, which can make treatment less effective. Still, even with this knowledge, finding treatments that work for everyone is a major challenge.
In our study, we created a version of pancreatic cancer in animals that let us observe what happens when the cancer comes back after treatment. We found that, even though the cancers looked different and acted differently, they shared some common weak points that help them survive. By testing which genes cancer cells rely on to stay alive, we discovered a group of genes that almost all of the cancers need, no matter their type.
These findings suggest that new treatments should focus on these shared weak spots, which could lead to therapies that work for more patients and make it less likely for the cancer to return.
Background & aimsPancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by frequent recurrence and resistance to both standard and targeted therapies. Transcriptomic profiling has defined distinct PDAC molecular subtypes with clinical significance; however, therapeutic strategies targeting subtype-specific vulnerabilities have been hindered by phenotypic plasticity. The coordinated dysregulation of non-mutated gene networks, a concept central to hallmark cancer behaviors, may underpin common genetic dependencies across molecularly distinct tumors. This study aimed to determine whether phenotypically diverse PDAC subtypes converge on shared transcriptomic programs and survival mechanisms.
MethodsA controlled model of PDAC recurrence was established by ablating oncogenic Kras expression in primary tumors, generating matched pairs of primary and recurrent tumors. Transcriptomic heterogeneity was characterized by bulk RNA sequencing and independent component analysis. A targeted in vivo pooled loss-of-function CRISPR screen was performed to functionally interrogate candidate genes identified as components of shared transcriptomic programs.
ResultsPrimary and recurrent PDAC tumors exhibited transcriptomic profiles spanning classical and basal-like subtypes, mirroring human disease. Independent component analysis identified gene expression signatures conserved across subtypes, indicating the presence of shared molecular programs. Functional screening revealed a set of genes essential for tumor cell survival irrespective of subtype or treatment history, demonstrating the existence of core genetic dependencies in PDAC.
ConclusionsThese findings demonstrate that molecularly distinct PDAC tumors converge on common genetic dependencies, suggesting that targeting shared survival mechanisms may provide a broadly effective therapeutic strategy for refractory disease.
KeywordsPancreatic cancer; Molecular subtypes; Transcriptomics; Recurrence; Genetic dependencies; CRISPR screen.
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