Abstract C113: The mitochondrial calcium uniporter supports epithelial to mesenchymal transition of pancreatic ductal adenocarcinoma

Abstract

Abstract In spite of many new developments in cancer treatments and targeted therapies over the past few decades, outcomes for pancreatic ductal adenocarcinoma (PDAC) patients continue to be poor. Calcium signaling and mitochondrial function are known to contribute to cancer outcomes in many paradigms, yet much remains unknown in the context of PDAC. The mitochondrial Ca2+ uniporter, MCU, is the main route by which mitochondria can take up Ca2+ into the mitochondrial matrix, where it drives metabolic activity in the tricarboxylic acid cycle and promotes ATP synthesis by the electron transport chain. Our previous work suggests that Ca2+ flux from the endoplasmic reticulum (ER) into the mitochondria at mitochondria-associated membranes (MAMs) may be important to drive malignancy. Here, we show that MCU expression is associated with poor outcomes in PDAC patients and disease progression in murine organoid models of cancer development. Further, deletion of Mcu in murine KPC cells results in ablation of mitochondrial Ca2+ uptake, which reduces growth, proliferation, and clonogenicity. Tumor growth and metastatic colonization are also reduced in orthotopic implantation models, with some KPCY-McucKO models failing to develop primary lesions. This suggests that MCU, and thus mitochondrial Ca2+, play an important role in tumor growth. Critically, we here elucidate a heretofore unknown relationship between ER-to-mitochondrial Ca2+ flux through Mcu and epithelial to mesenchymal transition (EMT), an important process that contributes to poor outcomes in PDAC. To this end, McucKO associates with reduced basal Snail expression and reduced TGFβ secretion, and McucKO clones have a more epithelial morphology than their isogenic, Mcu-expressing counterparts. Both stable expression of Snail and treatment with TGFβ are able to rescue growth, mobility, and clonogenic deficits in McucKO cell lines to levels comparable to isogenic, Mcu-expressing cell lines. Uptake assays, metabolomics, isotope tracing, and mRNA-Seq have enabled us to elucidate metabolic and transcriptional rewiring induced by Snail and TGFβ treatment which may promote cell survival and proliferation despite the lack of Mcu. This work has important implications for potential targeting of Ca2+ signaling in the context of PDAC. Citation Format: Jillian S. Weissenrieder, Jason Pitarresi, Natalie Weinmann, Rebecca Drager, Usha Paudel, Anil Rustgi, Ben Stanger, J. Kevin Foskett. The mitochondrial calcium uniporter supports epithelial to mesenchymal transition of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C113.