Abstract IA014: Collagen cleavage controls PDAC metabolism and malignancy via a DDR1-NRF2 cascade and mitochondrial biogenesis

Abstract PDAC is distinct by being highly desmoplastic, due to the activation and eventual infiltration of cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) they produce, which is mainly composed of collagen type I (Col I). The role of fibroblasts and collagen in PDAC pathology is highly contentious, ranging from tumor stimulatory to tumor inhibitory. Using mouse models and human specimens we found that the way in which Col I affects PDAC progression, metabolism and its response to therapy is highly dependent on its cleavage by matrix metalloproteases (MMP). Whereas noncleaved Col I inhibits PDAC metabolism, inhibits human and mouse PDAC growth in mice and is correlated with improved survival after surgical resection, MMP generated Col I fragments stimulate tumor metabolism and growth and correlate with poor post-resection survival. These differential activities of cleaved and noncleaved Col I depend on its interactions with the receptor tyrosine kinase DDR1. Whereas MMP-generated Col I binds DDR1 and activates it, intact Col I induces DDR1 degradation. By activating DDR1, cleaved Col I triggers an NF-kB-p62-NRF2 signaling cascade, whose major efferent, NRF2, controls many aspects of PDAC metabolism, including macropinocytosis, aerobic glycolysis, respiration and mitochondrial biogenesis. Inhibitors of NRF2 and mitochondrial biogenesis induce regression of established PDAC in-vivo and compromise its growth and survival in-vitro. Citation Format: Michael Karin, Hua Su. Collagen cleavage controls PDAC metabolism and malignancy via a DDR1-NRF2 cascade and mitochondrial biogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA014.