Abstract PO-105: The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis

Abstract

Abstract The multifunctional endocytic receptor low-density lipoprotein receptor-related protein (LRP)1 has recently been identified as a hub within a biomarker network for multicancer clinical outcome prediction. The mechanismhowLRP1 modulates cancer progression is poorly understood. In this studywe found that LRP1 and one of its ligands, tissue plasminogen activator (tPA), are expressed inmelanoma cells and control melanoma growth and lung metastasis in vivo. Mechanistic studies were performed on 2 melanoma cancer cell lines, B16F10 and the B16F1 cells, both of which formprimary melanoma tumors, but only B16F10 cells metastasize to the lungs. Tumor-, but not niche cell–derived tPA, enhanced melanoma cell proliferation in tPA2/2 mice. Gain-of-function experiments revealed that melanoma LRP1 is critical for tumor growth, recruitment of mesenchymal stem cells into the tumor bed, and metastasis. Melanoma LRP1 was found to enhance ERK activation, resulting in increased matrix metal-loproteinase (MMP)-9 RNA, protein, and secreted activity, a well-known modulator of melanoma metastasis. Restoration of LRP1 and tPA in the less aggressive, poorly metastatic B16F1 tumor cells enhanced tumor cell proliferation and led to massive lung metastasis in murine tumor models. Antimelanoma drug treatment induced tPA and LRP1 expression. tPA or LRP1 knockdown enhanced chemosensitivity in melanoma cells. Our results identify the tPA-LRP1 pathway as a key switch that drives melanoma progression, in part by modulating the cellular composition and proteolytic makeup of the tumor niche. Targeting this pathway may be a novel treatment strategy in combination treatments for melanoma. Citation Format: Beate Heissig, Yousef Salama, Taro Osada, Yuko Tsuda, Satoshi Takahashi, Koichi Hattori. The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-105.