Abstract Diffuse-type gastric cancer (DGC) shows strong interactions between cancer-associated fibroblasts (CAFs) and cancer cells through PDGF/PDGFR signaling. While PDGFR is expressed in CAFs, PDGF ligands were believed to be mainly secreted by cancer cells. However, DGC cohort analysis revealed a correlation between stromal fibrosis and platelet aggregation, suggesting that platelets may serve as an alternative PDGF source. This study aims to elucidate the mechanisms of interorgan crosstalk through GC fibrosis-bone marrow (BM) hematopoiesis-platelet axis. IL6 was particularly upregulated in DGC and correlated with fibrosis. We established an orthotopic model using IL6-overexpressing murine GC cells, which developed fibrotic tumors. Notably, platelets in peripheral blood of these mice showed increased count, size, and PDGFD concentration. Cell population analysis in BM revealed increased megakaryocyte progenitors and decreased erythroid progenitors, indicating IL6-induced hematopoietic imbalance. These findings suggest that IL6 promotes PDGFD-rich platelet production, contributing to tumor fibrosis. This study highlights a key role of BM-derived platelets to enhance tumor fibrosis in DGC. Citation Format: Akiho Nishimura, Takatsugu Ishimoto, Takashi Semba, Atsuko Yonemura. Novel mechanism of tumor fibrosis mediated by interorgan crosstalk 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 3365.
Nishimura et al. (Fri,) studied this question.