Abstract IA09: Collagen microenvironment in the modulation of local invasion and distal metastasis

Abstract

Abstract Metastasis is a multistep process that includes, but is not limited to, local invasion, intravasation of tumor cells into the circulation, and extravasation of circulating tumor cells from the circulation into distal organs for metastatic colonization. The 5-year survival rate of patients diagnosed with metastatic bladder urothelial carcinomas is less than 10%, posing a major clinical challenge. Previous studies in human bladder urothelial carcinomas have elegantly investigated the mechanistic contribution of tumor cell intrinsic properties that promote metastasis. However, the contribution of tumor microenvironments at both the primary tumor and metastatic sites to the metastatic process is not as well characterized. Historically, the extracellular matrix (ECM) was considered a passive scaffold, enclosing neighboring cancer cells and other cell types to support tissue architecture. Intriguingly, recent studies, including ours, revealed the emerging roles of ECMs as a dynamic component of the tumor microenvironment, which crosstalks with cancer cells. Here, we showed that bladder cancer cells expressing the collagen receptor CD167a or discoidin domain receptor 1 responded to collagen stimulation at the primary tumor to promote local invasion and utilized the same receptor to preferentially colonize at airway smooth muscle cells—another rich source of collagen and a newly identified metastatic niche in lung. Morphologically, these collagen-CD167a-driven metastatic foci are uniquely distinct from typical lung alveolar metastatic lesions and exhibited activation of the CD167a-HSP90-Stat3 axis. Interestingly, metastatic lung colonization could be abrogated using an investigational drug that attenuates Stat3 activity, implicating this seed-and-soil interaction as a therapeutic target for abrogating lung metastases. Together with our recent study demonstrating prevalent Stat3 expression in the primary basal bladder carcinomas (J Natl Cancer Inst 2018 May 1;110[5]:448-59), these findings implicate Stat3 as a valid target for metastatic bladder carcinoma patients with a basal molecular subtype, thus opening a new avenue for potential clinical intervention. Citation Format: Yu Cheng, Keith Syson Chan. Collagen microenvironment in the modulation of local invasion and distal metastasis [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA09.