Abstract PO-026: The mitochondrial calcium uniporter contributes to PDAC development and invasion

Pancreatic ductal adenocarcinoma (PDAC) has an exceptionally poor prognosis, with about 50,000 new cases and 45,000 deaths each year. While novel chemotherapeutics targeted to driver pathways and immune responses have increased the overall survival rate of cancer patients in general, these improvements are rarely seen in PDAC. PDAC often metastasizes early, and metastases ultimately lead to death in many PDAC patients. A stronger understanding of disease mechanisms and new therapeutic modalities are desperately needed to improve outcomes for many patients. Previously, we showed that cancer cell lines of multiple types are “addicted” to constitutive Ca++ flow into mitochondria through the mitochondrial calcium uniporter (MCU) at endoplasmic reticulum-mitochondria contact sites. We hypothesized that mitochondrial Ca++ influx through MCU contributes to cancer cell development, proliferation, and metastasis in PDAC by promoting metabolic activity within mitochondria. We now show that mRNA expression of MCU is elevated in a subset of pancreatic cancer patients, and high MCU protein expression correlates with poor survival outcomes. In addition, MCU gene expression is associated with the expression of a number of genes which associate with metastasis and/or poor survival outcomes, including ADAM proteins, KRAS, and RAC1. To further examine the role of MCU in PDAC, we used the Pdx1cre; KrasLSL-G12D/+; p53fl/+, Rosa26LSL-YFP/LSL-YFP; Mcufl/fl (KPCY) murine model of PDAC. We generated KPCY-McuKO (knockout) animals and cell lines from their YFP-positive tissues for further analysis. Cell lines developed from KPCY-McuKO pancreatic tissues fail to take up Ca++ into mitochondria in a manner that is rescued by stable re-expression of MCU. This Ca++ uptake is associated with an increase in pyruvate dehydrogenase activation. In these cells, MCU expression is also associated with an increase in cell motility, self-renewal capacity, and cell proliferation. Re-expression of MCU in these cells is associated with a morphological change to a more fibroblastic morphology indicative of epithelial to mesenchymal transition (EMT), including decreased surface expression of e-cadherin. These findings suggest that MCU may contribute to growth and metastasis. Indeed, in an immunocompetent, syngeneic orthotopic model of murine PDAC using one of these cell lines, tumor growth and metastasis were greatly ablated. Such results suggest that MCU-mediated influx of mitochondrial Ca++ contributes to PDAC development and metastasis and may present a therapeutic target for cancer treatment. Citation Format: Jillian S. Weissenrieder, Jason R. Pitarresi, Emily Fernandez-Garcia, Ben Z. Stanger, Anil K. Rustgi, J. Kevin Foskett. The mitochondrial calcium uniporter contributes to PDAC development and invasion [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-026.