Abstract 165: Spatially resolved mechanostress effects on tumor microenvironments: Tumor cells and fibroblasts in focus

Abstract Tumorigenesis is influenced by various environmental factors, including growth-induced solid stress and fluid pressure, both of which are key drivers of tumor progression and resistance to therapy. While certain tumors arise in regions exposed to significant weight-pressure, how macroscopic mechanostress affects the tumor microenvironment remains largely unclear. In this study, we showed that macroscopic mechanostress disrupts nuclear envelope integrity. Single-cell RNA sequencing data demonstrated that the macroscopic pressure shows changes in gene expression within tumor microenvironment cells and reshaped fibroblast subtypes.In spatial transcriptomics, using a distance-based tumor border detection model, we can determine spatially resolved fine layers of tumor margin and peritumor regions. We found an increased proportion of fibroblasts, especially Lrrc15-positive myofibroblasts, located in peritumor region facing the tumor border. We also showed upregulated metastasis signature and immune inhibitory signature indicating that mechanostress-driven transcriptional changes promote metastasis and resistance to immunotherapy. Using a mouse plantar melanoma model, we found that exogenous mechanostress, mimicked by genetic disruption of the nuclear lamina, induces nuclear envelope rupture in melanoma cells and increases the number of Lrrc15-positive myofibroblasts. Interestingly, these myofibroblasts further contribute to nuclear envelope rupture in melanoma cells, creating a feedback loop. Together, our findings highlight a critical role for mechanostress in cancer progression, driven by nuclear envelope damage and shifts in tumor-stromal interactions. Citation Format: Wooseok Kim, Hyunseok Kim, Minki Kim, Zhangxian Lan, Hyung-Soon Park, Mi Ryung Roh, Joon Kim, Jong-Eun Park. Spatially resolved mechanostress effects on tumor microenvironments: Tumor cells and fibroblasts in focus [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 165.