Abstract 6096: The microarchitecture and fibrillar collagen expression of leiomyosarcoma are associated with malignancy

The expression, abundance, and microarchitecture of fibrillar collagens are associated with tumor development and aggressiveness in various carcinomas. However, the impact of fibrillar collagens on mesenchymal tumors is less understood. While uterine leiomyomas, also known as fibroids, are characterized by high fibrillar collagen deposition and depend on ECM signaling for cell proliferation, the impact of fibrillar collagens on malignant uterine leiomyosarcomas has not been explored. Thus, identifying malignancy and aggressiveness-associated features of the fibrillar collagen-leiomyosarcoma crosstalk may provide novel biomarkers and therapeutic targets for these aggressive tumors. We used publicly available RNAseq data and performed RNAseq and picrosirius red analysis of fiber microarchitecture in a cohort of normal myometrium (MM; n =68 ), leiomyoma (LM; n = 66), and leiomyosarcoma (LMS; n = 67) tissues. Furthermore, we cultured patient-derived primary cells (4 MM, 3 LM, and 4 LMS) on collagen I-functionalized polyacrylamide gels at stiffness ranging from 0.5 to 115 kPa, covering the physiological and pathological stiffness, to investigate distinct behaviors between cell types, including proliferation, migration, and activity of the ECM stiffness molecular rheostat YAP/TAZ. At the protein level, analysis of fibrillar collagen microarchitecture revealed that LMS tumors present reduced fibrillar collagen density and hyphal growth units and enhanced fiber endpoints compared to both MM and LM. At the gene expression level, however, LMS tumors did not show reduced fibrillar collagen expression, instead they exhibited enhanced matrix metalloproteinase expression, particularly of MMP14. Furthermore, COL11A1 was specifically upregulated in LMS tumors and its expression was associated with poor prognosis. Finally, in vitro response of MM, LM, and LMS cells to collagen I at defined stiffness showed that LMS cell migration, proliferation, and subcellular localization of YAP/TAZ are less sensitive to substrate stiffness than in MM and LM cells, although the response varied between distinct donors. In conclusion, we show that LMS tumors typically present low fibrillar collagen protein expression likely due to enhanced degradation. In addition, collagen I adhesion and stiffness have a lower impact on malignant LMS cells than on MM and LM, which may explain their ability to grow in low-collagen microenvironments. Furthermore, this study shows that COL11A1 is a potential