Abstract 570: Soft extracellular matrix orchestrates gastric cancer progression by triggering RNF146-mediated AMOT degradation and YAP/TAZ-driven senescence in macrophages.

Abstract The mechanical properties of the tumor microenvironment (TME) are critical regulators of cancer progression. While the role of a stiff extracellular matrix (ECM) is well-established, how soft ECM—common in early or remodeled tumors—modulates immune function in gastric cancer remains elusive. This study unveils a complete mechano-immunological pathway wherein soft ECM drives tumorigenesis by inducing pro-tumorigenic senescence in tumor-associated macrophages (TAMs). We demonstrate that soft ECM initiates this cascade through cytoskeletal remodeling and F-actin depolymerization, which displaces Angiomotin (AMOT) from the actin network, increasing its cytoplasmic pool. The liberated AMOT is then specifically targeted by the E3 ubiquitin ligase RNF146, which is upregulated in TAMs in response to soft mechanical cues, leading to AMOT ubiquitination and proteasomal degradation. This degradation relieves the cytoplasmic sequestration of YAP/TAZ, enabling their nuclear translocation and transcriptional activation within TAMs. This mechanochemical reprogramming initiates a distinct senescence-associated secretory phenotype (SASP), characterized by elevated secretion of CCL2, IL-8, MMP-12, and TGF-β, which collectively promote tumor cell invasion, angiogenesis, and immunosuppression. Functional validation using co-culture assays and orthotopic gastric cancer models confirmed that RNF146-mediated AMOT loss is sufficient to induce senescence and accelerate tumor growth and metastasis. Conversely, myeloid-specific RNF146 knockout stabilized AMOT, suppressed the SASP, and potently inhibited tumor progression. Our findings thereby delineate a complete pathological axis in gastric cancer: from soft ECM sensing and cytoskeletal remodeling to RNF146-mediated degradation of displaced AMOT, YAP/TAZ-driven macrophage senescence, and ultimately tumor progression. This work resolves the long-standing paradox of soft ECM in cancer by mechanistically linking it to pro-tumorigenic immune senescence, and nominates the RNF146-AMOT axis as a novel and promising stromal target for therapeutic intervention. Citation Format: Guofei Deng, Yusheng Luo, Yuxi Pan, Xiaorong Lin, Yuzhi Zhang, Yuqing Lin, Fuhui Wang, Jiancheng Wang, Shuo Fang. Soft extracellular matrix orchestrates gastric cancer progression by triggering RNF146-mediated AMOT degradation and YAP/TAZ-driven senescence in macrophages [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 570.