Abstract 132: Collagen I triggers a GCN2-mediated integrated stress response to promote cancer cell survival

Abstract Bladder cancer (BLCA) is the 6th most commonly diagnosed cancer in the US. Despite recent advances, BLCA has a high recurrence rate. Increased deposition of the extracellular matrix Collagen I (Col I) is a hallmark of cancer progression and correlates with poor patient survival in BLCA. Recent studies have showcased the dynamic nature of Col I, which signals key pro-tumoral processes like immune evasion and metastasis. Interestingly, Col I limits nutrient access and oxygen to adjacent tumors in the tumor microenvironment. Cancer cells adapt to disadvantageous conditions by activating pathways such as the integrated stress response (ISR) to downregulate mRNA translation to promote survival. High activity of ISR and its related proteins in cancer cells also increase chemoresistance, dormancy and metastasis. How Col I plays a role in activating pro-survival ISR in BLCA remains to be investigated. In this study, we describe the direct role of Col I in exploiting ISR in BLCA, increasing its tumorigenic capacity. We uncover that Col I rapidly downregulates global mRNA translation by inducing ISR, while promoting spheroid size in vitro and tumor growth in vivo. Mechanistically, Col I induces intracellular amino acid deprivation thereby activating GCN2, an important amino acid sensor and a key kinase mediating ISR. Inhibition of GCN2 and subsequent ISR activity is an effective therapeutic target in multiple cancer types. Here, we show pharmaceutical inhibition of GCN2 disrupts ISR, rescuing translation while decreasing Col I-induced spheroid and tumor growth. Clinically, analysis of the TCGA BLCA dataset reveal both high expression of ISR-associated genes and a high GCN2-mediated signaling pathway score correlate with poor overall survival. GCN2 and ISR pathway scores also correlate with high Col I expression, further indicating their involvement in promoting BLCA tumorigenesis. These findings unravel a novel mechanism by which Col I utilizes the ISR pathway to promote BLCA tumorigenesis and provides a potential therapeutic targets for BLCA patients in the future. Citation Format: Mark Ellie De Boton Alonzo, Ethan Jadon Subel, Hongbo (Beth) Gao, Stephen QR Wong, Yung Hsing Huang, 2David Chang, 2Grace Wong, 2Mustafa Karabicici, 1Sung Yun Jung, 3Fotis Nikolos, 2Keith Syson Chan2. Collagen I triggers a GCN2-mediated integrated stress response to promote cancer cell survival [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 132.