Abstract 84: Dimerization of MACC1: A newly identified feature and its role in cancer metastasis

Abstract Cancer metastasis remains the most lethal characteristic of tumors mediating the majority of cancer-related deaths and continues to be a leading cause of mortality. Exemplified for colorectal cancer (CRC) metastasis results in around 0.9 million deaths annually worldwide. Identifying key molecules responsible for metastasis, understanding their biological functions and therapeutically targeting these molecules is therefore of tremendous value. Metastasis Associated in Colon Cancer 1 (MACC1), a gene first described in 2009, is such a key driver of metastatic processes, initiating cellular proliferation, migration, invasion, and metastasis in vivo. Since its discovery, the value of MACC1 as a prognostic biomarker has been confirmed and linked to poor overall outcome in more than 20 cancer types. Despite numerous studies identifying MACC1 as a promising target for solid cancer, little is known about the structural features of MACC1 protein and its oligomeric states. Therefore, we asked whether MACC1 can form protein complexes and if so, which region is critical for complexation/oligomerization. Using AlphaFold-Multimer, the MACC1 homodimer structure was predicted and the residues involved in dimerization were evaluated. The notion of MACC1 dimerization was validated further using bioluminescence resonance energy transfer (BRET) in HEK293 and HCT116 cell system. To our surprise, BRET revealed that MACC1 exists as homodimer in living cells. Further, we report that mutation of the predicted dimer interface residues Val212, Ile214 and Cys216 close to the N-terminus of MACC1 in the ZU5 domain hinders homodimerization and affects MACC1-mediated cell migration in vitro and metastasis formation in vivo. Taken together, these findings identify an important role of MACC1 dimers for the MACC1-mediated metastasis phenotype. We provide with this study a framework to better understand the MACC1 signaling landscape and to facilitate the rational development of novel therapies aiming at MACC1 oligomerization to intervene in MACC1-mediated metastasis. Citation Format: Malti Dumbani, Benedikt Kortüm, Simona Kostova, Fabian Zincke, Alexandra Forrai, Dennis Kobelt, Wolfgang Walther, Erich Wanker, Oliver Daumke, Christoph Buhlheller, Ulrike S. Stein. Dimerization of MACC1: A newly identified feature and its role in cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 84.