Abstract B61: Arousal of cancer-associated stromal fibroblasts: Palladin-activated fibroblasts promote tumor invasion.

Abstract

Background: Myofibroblasts, or cancer-associated fibroblasts (CAF), can produce tracks within the extracellular matrix which in effect, create tunnels for the carcinoma cells to follow. We undertook studies to identify the mechanism of how this fibroblast-led cancer invasion occurs in pancreatic cancer. Results: CAF express palladin, an embryonic and cytoskeletal protein, early in tumorigenesis at the dysplastic stage. Upregulation of palladin causes the normal fibroblast to develop a fusiform/mesenchymal shape with apparent invadopodia—feet that contain proteolytic enzymes. To identify the contents of the “feet” of palladin-activated myofibroblasts, we ensnared the myofibroblasts in the act of invasion in a sieve that was large enough to let the feet through but too small for a whole cell to pass through. Proteomic analysis performed on the ensnared and isolated “feet” revealed the overexpression of proteolytic enzymes such as metalloproteinases and cathepsin, invadopodia proteins, and proteins associated with poor prognosis in cancer. Functional studies demonstrated that, in the setting of an inflammatory or wounding signal, the palladin-activated fibroblasts can both rip and destroy the extracellular matrix literally creating tunnels through which the cancer cells can follow. Fibroblasts without palladin expression lack the ability to create the tunnels used by cancer cells. Activation of palladin in a normal fibroblast is caused by paracrine signaling from an adjacent ras-mutated epithelial cell. Affects of palladin on myofibroblasts are reversible with shRNA. Conclusion: Embryonic and cytoskeletal protein, palladin, activates myofibroblasts in pancreatic cancer to escort the cancer cells through tunnels created in the pancreas. The mechanism to create these escape tunnels occurs through the transformation of a fibroblast into a myfibroblast, the development of feet that contain invasive proteolytic proteins, and the ability to rip through the extracellular matrix. Citation Format: Teresa Averill Brentnall, Lisa Lai, Mary Bronner, Ru Chen. Arousal of cancer-associated stromal fibroblasts: Palladin-activated fibroblasts promote tumor invasion. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B61.