The effect of cancer cell produced collagen 1 homotrimers on DDR1 signaling activation by microenvironmental collagen 1 fragments.

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Abstract This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. Pancreatic Ductal Adenocarcinoma (PDAC) accounts for over 90% of pancreatic malignancies and is the third leading cause of cancer mortality in the United States. Elucidating the biology of this pernicious cancer remains the key to improving prognosis for patients. PDAC is characterized by a complex desmoplastic stroma composed largely of fibroblasts and extracellular matrix (ECM), that can function to either restrain or promote tumor progression. Type 1 Collagen (Col I), typically a heterotrimer consisting of two a1 and one a2 chains, is the major ECM protein found in the PDAC-associated stroma, and in recent years, has been proven to play an important role in regulating tumor growth, progression, and response to therapy through the discoidin domain receptor tyrosine kinase 1 (DDR1) and a3b1 integrin receptor signaling pathways. The Karin lab discovered that insoluble and intact Col I fibrils in the ECM are cleaved by matrix metalloproteinases (MMPs) to form soluble ¼ and ¾ Col I fragments. Unlike intact Col I fibrils, which induce DDR1 degradation and inhibit DDR1’s downstream effectors, the ¾ Col I fragment binds to DDR1, activates its tyrosine kinase activity and stimulates PDAC metabolism, mitochondrial biogenesis, and tumor growth. The Kalluri lab, however, discovered that PDAC cancer cells epigenetically silence the COL1A2 gene to produce small amounts of MMP-resistant Col1a1 homotrimers consisting solely of three a1 chains, unlike the heterotrimer normally produced by cancer associated fibroblasts (CAF) in the PDAC stroma. The homotrimer changes the immune landscape by altering the tumor microbiome and stimulates tumor growth in an autocrine manner through a3b1 integrin receptor mediated oncogenic signaling. The effect of cleaved and intact Col I heterotrimers that constitute a majority of the PDAC ECM and act via DDR1 on Col I homotrimer modulation of cancer cell growth via a3b1 integrin and vice versa is a critical biological and translational question that is yet to be answered. This proposal addresses the gap in our understanding of Col I function in PDAC using two aims. The first aim focuses on whether Col Ia13 homotrimers produced by PDAC cells can activate or inhibit DDR1 signaling in the presence of intact and/or cleaved Col I heterotrimers. The second aim determines how Col Ia13 expressing and Col Ia1-null PDAC cells respond to ECM containing cleavable and non-cleavable Col I heterotrimers. Deciphering the mechanistic interplay between the Col I subtypes identified in the PDAC ECM is a critical step in designing successful stroma- targeting treatments for pancreatic cancer.