Our limited knowledge of the biological mechanisms that lead to the initiation and progression of pancreatic cancer represents a fundamental gap in our understanding of this disease. Without this knowledge, our ability to rationally develop effective treatments for this disease is extremely limited. My long-term goal is to understand the genetic mechanisms that drive pancreatic carcinogenesis. To this end, my overall objective for this specific proposal is to determine both the cellular and molecular function of KDM6A, which has recently been uncovered as a promising novel candidate tumor suppressor of pancreatic cancer. Two important questions remain unanswered: 1) which stage(s) of pancreatic carcinogenesis are affected by the loss of Kdm6a, and 2) is Kdm6a's tumor-suppressive activity dependent on its canonical function as a histone demethylase, or is it independent of its demethylase function? The rationale for this proposal, which addresses these questions, is that it will generate fundamental insights into the biology of pancreatic cancer, which is predicted to surpass both colorectal and breast cancer to become the 2nd leading cause of cancer death in the U.S. by 2020. Based on existing data, my central hypothesis is that loss of Kdm6a drives the proliferation and metastatic proclivity of pancreatic cancer cells in a demethylase-independent manner. To address my central hypothesis and accomplish my overall objective, I will pursue two specific aims:
Aim 1) Determine the effect of Kdm6a loss on tumor initiation, progression, and metastasis in a novel mouse model of pancreatic cancer;
and Aim 2) Uncover the role of Kdm6a demethylase-activity on its tumor-suppressive function in pancreatic cancer cells.
For Aim 1, I will use a CRISPR-based mouse model that I recently co-developed to inactivate Kdm6a during pancreatic tumorigenesis.
For Aim 2, I will perform comprehensive in vitro and in vivo assays on Kdm6a-null pancreatic cancer cell lines re-expressing either wild type or demethylase-deficient Kdm6a to determine whether the demethylase activity of Kdm6a is required for its tumor-suppressive function. I believe this research strategy is innovative because it leverages unique methodological approaches to address important questions surrounding pancreatic cancer biology that are otherwise prohibitively difficult to test. As a result, this proposal is expected to enable novel avenues of cancer research beyond those described in this application. The research proposed here is significant because it will strategically push forward and expand the boundaries of our knowledge of pancreatic cancer. Ultimately, this knowledge has the potential to inform the next generation of precisely targeted therapeutics that will reduce the burden of cancer in the United States.
The research proposed here is relevant to public health since knowledge of the fundamental mechanisms that cause cancer is expected to drive the development of novel diagnostic, therapeutic, and palliative strategies that are so urgently needed. The proposed research is relevant to the mission of the NIH, which in part focuses on generating fundamental biological insights that will directly contribute to improving human health.
|Winters, Ian P; Chiou, Shin-Heng; Paulk, Nicole K et al. (2017) Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity. Nat Commun 8:2053|