Cancer metastasis is a complex multistep process, involving the detachment of cancer cells from the primary tumor, intravasation, survival in the bloodstream, extravasation, and establishment of new foci in distant organs. Changes in cell-cell and cell-matrix adhesion accompany the transition from benign tumors to invasive, malignant cancer and the subsequent metastatic dissemination of tumor cells. Cadherins are a family of cell adhesion molecules expressed in a tissue specific manner in normal tissues. E-cadherin is responsible for maintaining the normal organization of the epithelia and is often downregulated in metastatic tumors. In contrast, de novo expression of N-cadherin is often observed in tumors of epithelial origin. N-cadherin alters the cellular behavior of breast cancer cells in culture rendering them more motile and invasive. Cadherin subtype switching (E-cadherin to N- cadherin) is a hallmark of tumor progression, yet it is poorly understood how N-cadherin affects tumor cell behavior in vivo. We generated an N-cadherin conditional knockout (CKO) mouse (conventional N-cadherin KO is embryonic lethal), providing an opportunity to examine the requirement for N- cadherin in tumor progression and metastasis in a genetically defined animal model. The N-cadherin CKO model was combined with a novel pancreatic ductal carcinogenesis model that targets mutant K-ras to pancreatic progenitor cells. This animal model recapitulates the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDA) observed in human patients with pancreatic cancer. We describe in vivo evidence that loss of N-cadherin results in increased tumorigenesis. Based on these preliminary data, we hypothesize that loss of N-cadherin- mediated adhesion/signaling relieves cell contact inhibition of cell growth by altering the actin cytoskeleton. This hypothesis will be pursued by the following interrelated Specific Aims: (1) To characterize the progression of PanIN to PDA in the absence of N-cadherin;(2) To evaluate the effects of loss of N-cadherin on the cytoskeletal regulator, RhoA;(3) To determine the role of focal adhesions in the regulation of N-cadherin-mediated contact inhibition of cell growth. This exploratory R21 grant will determine the consequences of genetically blocking the switch from E-cadherin to N- cadherin in pancreatic cancer. Understanding the molecular mechanisms underlying the progression of pancreatic cancer may provide insight for the development of novel antineoplastic therapies.
Our unexpected finding that loss of N-cadherin leads to increased PanIN development in K-rasG12D;N-cadflox/flox;Pdx1-Cre mice provides an entry point to uncover novel molecular mechanisms regulating tumor growth. Furthermore, a better understanding of N-cadherin function in vivo is imperative given that the N-cadherin antagonist, ADH-1, is now in Phase IIb clinical trial (www.adherex.com). Understanding the molecular mechanisms underlying the progression of pancreatic cancer may provide insight for the development of novel antineoplastic therapies.
| Su, Y; Li, J; Witkiewicz, A K et al. (2012) N-cadherin haploinsufficiency increases survival in a mouse model of pancreatic cancer. Oncogene 31:4484-9 |
