Abstract 4916: MUC13 enhances anchorage independent survival and cooperates with YAP1 and β-catenin towards colorectal cancer metastasis
Authors: Kyle Doxtater, Radhika Sekhri, Utkarsh Mishra, Meena Jaggi, Manish Tripathi, Subhash Chauhan
Journal: Cancer Research (2020)

Abstract Colorectal Cancer (CRC) is the 3rd most common and deadliest cancers in the United States. About 90% of all cancer related deaths are due to the development of metastatic sites in the body. Metastasis develops slowly over time, due to it being an inefficient process and having to overcome several natural defenses, anchorage independent growth aka Anoikis, being one of them. Understanding the mechanism overcoming Anoikis will help develop new therapeutic options to prevent the metastatic spread of cancer cells. Low adhesion cell culture model was developed and standardized to study the key pathways and proteins responsible for anchorage independent survival and metastasis progression in CRC. We identified mucin MUC13 in correspondence with YAP1 and β-catenin as key upregulated proteins in anchorage independent survival and metastasis progression. In an isogeneic CRC cell line model, overexpression of MUC13 in non-metastatic SW480 cells (originally expressing minimal MUC13) increased anchorage independent survival and enhanced tumorigenesis compared to SW480+Vector cells. Metastatic SW620 CRC cells (highly expressing MUC13) showed a decreased anchorage independent survival and tumorigenesis after knockdown using specific shRNA targeted against MUC13, compared to its vector. When co-cultured with fibroblast cells SW480+MUC13 cells showed an increase in spheroid size and percentage of live cells after 36hrs as compared to control cells. A decrease in spheroid size and live cells was observed with SW620+shMUC13 cells, compared to its control. We also observed an upregulation of key downstream β-catenin target genes c-Myc, Axin2 and an increase in YAP1 expression in MUC13 over-expressing cells. With MUC13 overexpression we observed and increase in the formation of YAP1/β-catenin survival complex within the nucleus at 36hrs compared to SW480+Vector. Enhanced interaction between MUC13/YAP1 and MUC13/β-catenin in the nucleus was also observed. In human CRC tissues, MUC13 and YAP1 expression was high in tumor compared to normal adjacent tumor. MUC13 and YAP1 expression in human CRC tissue was highest at Stage II. However, highest YAP1 expression was observed while MUC13 and/or β-catenin present in the nucleus. This supports the notion that MUC13 is a key factor in enhancing anchorage independence survival and CRC tumorigenesis through cooperation with YAP1 and β-catenin. This study for the first time demonstrates complex formation between MUC13, YAP1 and β-catenin, and define their role in CRC progression and metastasis. Citation Format: Kyle Doxtater, Radhika Sekhri, Utkarsh Mishra, Meena Jaggi, Manish Tripathi, Subhash Chauhan. MUC13 enhances anchorage independent survival and cooperates with YAP1 and β-catenin towards colorectal cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4916.