Abstract 5101: Collagen I helps maintain cancer dormancy under metabolic stress

Abstract Cancer progression is driven by a combination of intrinsic and extrinsic stresses and reciprocal interactions between cancer cells and the extracellular matrix (ECM). Type I collagen is the most abundant ECM component in the human body. One hallmark of cancer progression is the elevated deposition and cross-linking of collagen, which regulates various cellular processes, including migration, proliferation, and apoptosis. Here, we report that under metabolically stressed conditions, cancer cells directly consume collagen to survive. Nutrient deprivation suppressed cell proliferation, evidenced by decreased levels of PNCA and Ki67 as measured by RT-PCR and confirmed by EdU immunofluorescence assay. Intriguingly, there was a significant increase in cancer stem cell (CSC)-associated markers -CD133, Sox2, Nanog, Oct4, ALDH1-at both mRNA and protein levels, compared to normal culture control. This trend persisted in cells cultured in both serum-free and exhausted (low pH and nutrient-derived) media, suggesting that metabolic stress from nutrient deprivation promotes cancer cells into a dormant and de-differentiated state. Notably, cells cultured on collagen gels showed superior survival under all conditions. In addition, cellular quiescence was confirmed via increased expression of p27 and a higher percentage of cells entered G0-G1 cell cycle arrest in the absence of collagen (∼90%) compared to those on collagen gels (∼70%). This pattern was consistent with the lower CSC expression observed in collagen gels, suggesting that collagen not only supports cell survival but may also act as a nutrient reservoir to mitigate metabolic stress. By employing a perfusion-enabled 3D patient-derived ex vivo model developed in our laboratory, we demonstrated significantly higher metabolic activity in the microtumors cultured in collagen-conjugated scaffold and active media transport, compared to static conditions. This was evidenced by increases in total cell number, percent viability, and EdU-positive cells. We also conducted long-term continuous confocal time-lapse imagings revealing that cancer cells actively uptake FITC-conjugated collagen for survival, enabling them to remain quiescent for up to 36 days. We were able to track and monitor cell activities at the same regions of interest over time to demonstrate cellular dormancy. This study provides compelling evidence that metabolic stress triggers a dormant phenotype in cancer cells, with enhanced stemness potential for cancer re-initiation and relapse. Our findings suggest that type I collagen acts as a vital nutrient reservoir for cancer cells under metabolic stress, aiding in the maintenance of their dormant state. Citation Format: Laxmi Swetha Karanam, Zoe Zhou, Said J. Cifuentes Maury, Marilena Tauro, Conor C. Lynch, Duy T. Nguyen. Collagen I helps maintain cancer dormancy under metabolic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5101.