Only a small number of genes are bona fide oncogenes and tumor suppressors such as Ras, Myc, p53 and PTEN. However, targeting these cancer drivers frequently fail to demonstrate sustained cancer remission. Tumor heterogeneity and evolution contribute to cancer resistance and pose challenges for cancer therapy due to differential gene expression profiles driving distinct tumor responses to treatments. Here we report that intratumor heterogeneity of Wnt/β-catenin/armadillo modulator δ-catenin controls individual cell behavior to promote cancer. The differential intratumor subcellular localization of δ-catenin mirrors its compartmentalization in prostate cancer xenograft cultures as a result of mutation-rendered δ-catenin truncations. Wildtype and δ-catenin mutants displayed non-overlapping protein interactomes that highlight rewiring of signal networks. Localization specific δ-catenin mutants influenced p120ctn-dependent Rho GTPase phosphorylation and shifted cells towards bFGF-responsive growth, a known signal to bypass androgen receptor dependence. Mutant δ-catenin promoted Myc-induced prostate tumorigenesis by increasing proliferation over apoptosis as well as β-catenin stabilization and HIF-1α expression. Therefore, intratumor δ-catenin heterogeneity by genetic remodeling promotes prostate cancer expansion towards androgen independence, supporting a neomorphism model paradigm for targeting tumor progression.

Citation Format: Mingchuan Li, Jongdee Nopparat, Jiao Zhang, Byron J. Aguilar, Yan-Hua Chen, Jie Du, Xin Ai, Yong Luo, Yongguang Jiang, Christi Boykin, Qun Lu. Intratumor δ-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer cell fate and behavior [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2904.