SWI/SNF is a multi-subunit chromatin remodeling complex that repositions nucleosomes to control access to DNA, thus regulating gene expression. Recently, we discovered focal DNA deletions and deleterious mutations that target SWI/SNF subunits in more than one-third of human pancreatic cancers, a frequency approaching that of TP53 mutation. SWI/SNF re-expression studies support a growth-suppressive function, and our preliminary data nominate polycomb repressive complex 2 (PRC2) antagonism and TGF? signaling as possible downstream effector pathways. SWI/SNF has also been reported to function in DNA damage repair, and our preliminary data show SWI/SNF loss sensitizes pancreatic cells to DNA damage. Building from these findings, the broad goals of the proposed studies are to define the pathways and mechanisms by which SWI/SNF alterations contribute to pancreatic cancer, and to identify therapies that might selectively target SWI/SNF-deficient pancreatic cancers. To achieve these goals, in Aim 1 we will investigate the role of PRC2 antagonism as a mediator of SWI/SNF growth suppression, by molecular studies of PRC2 in SWI/SNF-deficient and reconstituted pancreatic cancer cells, and in primary pancreatic tumors.
In Aim 2, we will similarly assess the role of TGF? signaling in mediating SWI/SNF growth suppression.
In Aim 3, we will determine whether residual SWI/SNF complexes (remnants of SWI/SNF alteration) contribute to growth phenotypes in pancreatic cancer cells. Finally, in Aim 4 we will evaluate possible therapies selective to SWI/SNF-deficient pancreatic cancers, starting with DNA damaging agents (to exploit the reported role of SWI/SNF in DNA damage repair) in cell viability assays. Completion of these studies should establish the pathways and mechanisms by which SWI/SNF alterations drive pancreatic cancer, and define therapeutic strategies for SWI/SNF-deficient pancreatic cancers. Given that SWI/SNF alterations are commonplace in pancreatic cancer, that almost nothing is known of their consequence (for example compared to TP53 mutations), and that pancreatic cancer is such a devastating disease, the proposed studies are expected to make a high-impact contribution to the field. Moreover, findings are likely to be extendable to other cancer types with SWI/SNF mutations.

Public Health Relevance

Pancreatic cancer is a recalcitrant disease with a dismal survival rate;as such, new molecular understanding and targeted therapies are urgently needed. My laboratory has discovered alterations of the SWI/SNF chromatin remodeling complex in a large fraction of pancreatic cancers. The proposed studies will determine how those alterations contribute to pancreatic cancer, and identify therapies that target pancreatic cancers with SWI/SNF alterations.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Okano, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code