Project description:RNA-seq profiling was conducted on human pancreatic cancer cell lines We measured the transcriptome in 14 human pancreatic cancer cell linees
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
Project description:<p>Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated in ADM lesions compared to normal tissue from human samples. Comprehensive metabolic assessment in three mouse models with pancreas-specific activation of KRAS, PI3K or MEK1 using Seahorse measurements, NMR metabolome analysis, mass spectrometry, isotope tracing and RNA-seq analysis revealed a switch from oxidative phosphorylation to glycolysis in ADM. Blocking the metabolic switch attenuated ADM formation. Furthermore, mitochondrial metabolism was required for de novo synthesis of serine and glutathione but not for ATP production. MYC mediated the increase in GSH intermediates in ADM, and inhibition of GSH synthesis suppressed ADM development. This study thus identifies metabolic changes and vulnerabilities in the early stages of pancreatic carcinogenesis.</p>
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a disease characterized by extensive resistance to conventional therapies, making clinical management a significant challenge. As cancer progresses, developmental signals are often aberrantly re-activated, driving the self-renewal of cancer cells and fueling therapy resistance. To understand the epigenetic regulators that may be required to sustain these aggressive cells, we carried out a focused screen and identified SMARCD3 as a new functional dependency in pancreatic cancer. SMARCD3, a subunit of the SWI/SNF nucleosome remodeling complex, was uniquely up-regulated in PDAC stem cells and amplified in human cancer. Using a dual-recombinase model of pancreatic cancer, we showed that stage-specific conditional genetic deletion of Smarcd3 preferentially impaired growth of established tumors, improving survival and synergizing with chemotherapy. Consistent with this, SMARCD3 was required for the in vivo propagation of patient-derived xenografts. Mechanistically, we found that SMARCD3 is incorporated in the BAF complex variant of SWI/SNF. Using comprehensive ChIP-seq analysis to map the SMARCD3-dependent epigenome we showed that Smarcd3 inhibition drives global losses in histone acetylation and BAF binding at active enhancers co-bound by FOXA1. Integrating this with RNA-seq analysis, we found that SMARCD3-BAF regulated a network of genes implicated in diverse programs converging on lipid homeostasis. Specifically, Smarcd3 deletion in vivo inhibited fatty acid metabolism, which is known to be enriched within therapy-resistant cancer cells. These data collectively identify SMARCD3 as a critical dependency in PDAC and link SWI/SNF with the epigenetic control of cell state and metabolism in PDAC.