Abstract 6007: Fibroblast-driven IGF1 signaling suppresses CD44 and promotes tumor cell senescence at the invasive front of colorectal cancer

Abstract Senescent tumor cells are cancer cells that undergo cell-cycle arrest in response to diverse intrinsic and extrinsic stresses. In our previous study, we observed that senescent tumor cells are preferentially enriched at the invasive front of colorectal cancer, where they display a marked global reduction in CD44 expression—including both standard and variant isoforms—an important hyaluronic-acid receptor associated with stress tolerance and redox resistance. Single-cell RNA-seq-based ligand-receptor interaction analysis revealed that senescent tumor cells are highly active in both sending and receiving intercellular signals. Among these, IGF1-IGF1R signaling between fibroblasts and senescent tumor cells was prominently upregulated.Mechanistically, activation of IGF1R triggered downstream AKT signaling, which suppressed CD44 transcription in tumor cells. Loss of CD44, a major regulator of cellular oxidative stress buffering, led to increased intracellular ROS levels. Elevated ROS subsequently downregulated DNMT1 expression, resulting in reduced methylation of the p16INK4a promoter and robust induction of p16INK4a, thereby driving tumor cells into a senescent state. Consistent with this mechanism, in vitro treatment with recombinant human IGF1 or co-culture with fibroblasts induced AKT activation, decreased CD44 levels, increased ROS, and ultimately promoted p16 expression.Together, these findings identify a previously unrecognized tumor-stromal crosstalk in which fibroblast-derived IGF1 activates the IGF1R-AKT-CD44-ROS-DNMT1-p16INK4a axis to promote tumor cell senescence at the invasive front. This stromal-driven process suggests that the invasive front is not merely a region of physical invasion but an active signaling niche where fibroblasts dictate tumor cell fate. Our study highlights this signaling cascade as a key regulatory mechanism shaping senescence, redox biology, and phenotypic plasticity in colorectal cancer progression. Citation Format: Tae Jun Park, Hee Young Kang, Jang Hee Kim, Seok Yun Kang, Hyun Woo Lee, Sang Wun Kim, Hong Seok Kim, Soon Sang Park. Fibroblast-driven IGF1 signaling suppresses CD44 and promotes tumor cell senescence at the invasive front of colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6007.