Abstract B017: Tumor-secreted collagen VI weakens endothelium and promotes metastasis

Abstract Metastasis is the leading cause of cancer-related deaths. However, the mechanisms behind the metastatic cascade remain poorly understood. Tumor’s metastatic potential is strongly influenced by microenvironmental cues such as low oxygen (hypoxia). Our published work reported that lung metastases in sarcoma are associated with increased primary tumor expression of the hypoxia-inducible collagen-modifying lysyl hydroxylase, Plod2; in multiple subtypes of sarcoma, excessive collagen lysyl hydroxylation results in secretion of immature collagen aggregates able to physically associate with tumor cells and promote both intravasation and extravasation. In the current study, we observed that Plod2 is colocalized with collagen VI and is important for its extracellular network structure, suggesting that collagen VI is a putative substrate of Plod2. Using an impedance sensing assay and a zebrafish intravital microinjection model, we demonstrated that tumoral Plod2 and collagen VI weaken the endothelial barrier and promote extravasation. With a tail vein injection mouse model, we determined that collagen VI is essential for lung metastasis. Clinically, we detected high levels of collagen VI in metastatic sarcoma in surgically resected patient lungs. Furthermore, by analyzing patient data in The Cancer Genome Atlas (TCGA), we found a strong correlation between the expression of both PLOD2 and collagen VI with disease outcomes. Together, our study identifies a novel mechanism of sarcoma lung metastasis, opening up opportunities for therapeutic intervention. Citation Format: Ying Liu, Ashley M. Fuller, Ileana Murazzi, Ann Devine, Nicolas Skuli. Tumor-secreted collagen VI weakens endothelium and promotes metastasis [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B017.