MERIT Award Recipient: Murray Korc, M.D.
Dysregulation of TGF Beta Action Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States. The cancer cells in this aggressive malignancy exhibit a high frequency of mutations in the Kras oncogene, a molecular "switch" that allows growth promoting signaling to be sustained. The same cells also express high levels of many tyrosine kinase receptors, which are the "engines" that promote the cells to proliferate. Work from our laboratory has suggested that these alterations, akin to an accelerator that is stuck at full thrust, drive the cancer cells ever faster along pathways that enhance their growth and metastasis. Concomitantly, pancreatic cancer cells are resistant to growth inhibition, especially in relation to the actions of transforming growth factor beta (TGF-β) molecules. This loss of negative growth constraints is due, in part, to the presence of mutations in the Smad4 gene and to the tendency of pancreatic cancer cells to overexpress a protein called Smad7. In parallel, there is increased production of all three TGF-β isoforms, and this overexpression has been correlated with disease progression and early cancer recurrence following tumor resection.
TGF-βs enhance pancreatic growth in vivo by promoting the proliferation of tumor blood vessels, cancer associated fibroblasts, and pancreatic stellate cells, and by suppressing cancer directed immune mechanisms. Moreover, high Smad7 levels suppress TGF-β-mediated growth inhibition without attenuating TGF-β's ability to induce the expression of metastasis-promoting genes, raising the possibility that Smad7 acts directly on the cancer cells to exert deleterious effects in PDAC. The current project addresses the mechanisms whereby Smad7 exerts these effects. We propose that Smad7 synergizes with oncogenic Kras. Our studies will take advantage of the availability of cultured human pancreatic cancer cell lines to analyze Smad7 actions. A mouse model will also be generated in order to determine whether Smad7 synergizes in vivo with constitutively active Kras to promote pancreatic cancer progression and metastasis. Because high Smad7 levels lead to the functional inactivation of pRb, a potent tumor suppressor gene that is not mutated in PDAC, we will also study the role of pRb in a mouse model.
The current proposal impacts public health in several ways. First, PDAC is a deadly malignancy, and the findings from this proposal will advance our understanding of the mechanisms that contribute to PDAC initiation, progression, growth and metastasis. Second, by advancing our knowledge of the role of Smad7 and Kras interactions in PDAC, the present studies will further our knowledge of the pathogenesis of PDAC and allow us to determine whether targeting Smad7 and/or its downstream effectors may prevent apoptosis resistance and drug resistance. Third, the proposed studies have the potential to pave the way toward novel diagnostic and therapeutic approaches that have not been previously considered.