Metastasis and chemoresistance—the two main reasons for the high mortality of cancer—are associated with a form of cellular plasticity known as epithelial-to-mesenchymal transition (EMT). Cancer cells undergoing EMT become invasive, facilitating metastasis, and undergo a shift in their vulnerability to antineoplastic drugs. In recent work, it has been shown that EMT does not involve a single mechanism but rather a diversity of programs, yielding a continuum of cell phenotypes along the epithelial-mesenchymal spectrum. We previously developed a lineage-traced model of pancreatic ductal adenocarcinoma (PDA) to study EMT in the context of stochastically-arising tumors. As expected, epithelial-mesenchymal plasticity in some tumors involves transcriptional repression of the epithelial state, resulting in a “classical EMT” (C-EMT) phenotype. Surprisingly, however, epithelial-mesenchymal plasticity in the majority of tumors involves post-transcriptional repression of the epithelial state, resulting in a “partial EMT” (P-EMT) phenotype. These two plasticity programs are associated with other aspects of tumor biology as well, including distinct modes of cellular invasion. Here, we identify calcium signaling in pancreatic cancer cells as a regulator of the P-EMT phenotype. Prolonged calcium flux induces PDA cells to remove E-cadherin (ECAD) and other epithelial proteins from the surface and relocalize it intracellularly. This loss of the epithelial phenotype occurs without changes in the abundance of mRNAs for these proteins, reminiscent of the P-EMT phenotype observed in tumors in vivo. In addition, inhibition of the calcium-signaling protein calmodulin blunts this EMT-inducing effect. These results implicate calcium signaling as a mediator of partial EMT phenotypes.

Citation Format: Robert J. Norgard, Ravikanth Maddipati, Nicole M. Aiello, David Balli, Jason R. Pitarresi, Derick N. Rosario-Berrios, Jinyang Li, Salina Yuan, Taiji Yamazoe, Yogev Sela, Allyson J. Merrell, Maximilian D. Wengyn, Kathryn Sun, Anil K. Rustgi, Ben Z. Stanger. Calcium signaling induces a partial EMT in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B38.