PXD038216
PXD038216 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | pbSMARCD3 is a key epigenetic dependency for pancreatic adenocarcinoma |
| 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. |
| HostingRepository | MassIVE |
| AnnounceDate | 2022-11-18 |
| AnnouncementXML | Submission_2022-11-18_17:32:39.765.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Supported dataset by repository |
| PrimarySubmitter | Jolene Diedrich |
| SpeciesList | scientific name: Mus musculus; common name: house mouse; NCBI TaxID: 10090; |
| ModificationList | No PTMs are included in the dataset |
| Instrument | Orbitrap Fusion Lumos |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2022-11-18 16:59:03 | ID requested | |
| ⏵ 1 | 2022-11-18 17:32:40 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: pancreatic cancer, epigenetics, SWI/SNF, Smarcd3, cancer stem cell, metabolism |
Contact List
| Diana Hargreaves | |
|---|---|
| contact affiliation | Salk Institute |
| contact email | dhargreaves@salk.edu |
| lab head | |
| Jolene Diedrich | |
| contact affiliation | SALK |
| contact email | jdiedrich@salk.edu |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive.ucsd.edu/MSV000090744/ |
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