Abstract 5940: The HU177 collagen neo-epitope regulates nuclear YAP accumulation and melanoma tumor growth and metastasis in vivo
Authors: Han Xianghua , Caron Jennifer M. , Brooks Peter C. 
Published: July 2017

The extracellular matrix (ECM) plays a central role in controlling cellular behavior and integrin receptors play key roles in this process. Significant molecular insight is available on how structurally intact forms of collagen regulate integrin-signaling, however unique collagen neo-epitopes can be generated during tumor development and these neo-epitopes may differentially bind to integrin receptors. These findings raise an interesting question as to whether signaling initiated by collagen neo-epitopes as compared to intact collagen, differentially modify the final signaling out-put. Integrin A10B1 is a receptor for the HU177 collagen neo-epitope, however, little is known about the down stream signaling events stimulated by this receptor-ligand interaction. We provide evidence that melanoma cell interaction with denatured collagen results in enhanced adhesion and migration. Talin is a molecule that facilitates integrin-associated linkages to the cytoskeleton and helps govern adhesive cellular processes. Melanoma cell interactions with denatured as compared to intact collagen, resulted in enhanced Talin phosphorylation and surprisingly increased the levels of Cyclin Dependent Kinase 5 (CDK5), a molecule implicated in Talin phosphorylation and motility. Melanoma cell interactions with denatured collagen also led to elevated nuclear accumulation of the Yes-associated protein YAP. Given these results, we examined the effects of anti-HU177 antibody on adhesion and migration. Targeting the HU177 neo-epitope inhibited cell adhesion and migration on denatured collagen and also inhibited YAP nuclear accumulation. Knocking down YAP in melanoma cells resulted in the generation of cells that were resistant to the inhibitory effects of anti-HU177 antibody, suggesting that part of the inhibitory activity of anti-HU177 antibody may be associated with its ability to alter YAP activity. We next examined the role of the HU177 neo-epitope and its receptor, A10B1, on melanoma tumor growth and metastasis. Targeting the HU177 neo-epitope inhibited tumor-angiogenesis, accumulation of ASMA positive stromal cells in melanomas and tumor growth in vivo. Importantly, knock down of A10B1, or direct targeting of the HU177 neo-epitope inhibited experimental metastasis of melanoma cells. Taken together, these studies provide new insight into the role of the HU177 collagen neo-epitope in melanoma tumor growth and metastasis and provide a novel strategy to inhibit melanoma progression through selective targeting of a A10B1 ligand, rather than the integrin itself.

Citation Format: Xianghua Han, Jennifer M. Caron, Peter C. Brooks. The HU177 collagen neo-epitope regulates nuclear YAP accumulation and melanoma tumor growth and metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5940. doi:10.1158/1538-7445.AM2017-5940