| First Author | Li M | Year | 2020 |
| Journal | Oncogene | Volume | 39 |
| Issue | 22 | Pages | 4358-4374 |
| PubMed ID | 32313227 | Mgi Jnum | J:290473 |
| Mgi Id | MGI:6441217 | Doi | 10.1038/s41388-020-1281-9 |
| Citation | Li M, et al. (2020) Intratumor delta-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer progression. Oncogene 39(22):4358-4374 |
| abstractText | Only a small number of genes are bona fide oncogenes and tumor suppressors such as Ras, Myc, beta-catenin, p53, and APC. 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 genomic rearrangement and expression driving distinct tumor responses to treatments. Here we report that intratumor heterogeneity of Wnt/beta-catenin modulator delta-catenin controls individual cell behavior to promote cancer. The differential intratumor subcellular localization of delta-catenin mirrors its compartmentalization in prostate cancer xenograft cultures as result of mutation-rendered delta-catenin truncations. Wild-type and delta-catenin mutants displayed distinct protein interactomes that highlight rewiring of signal networks. Localization specific delta-catenin mutants influenced p120(ctn)-dependent Rho GTPase phosphorylation and shifted cells towards differential bFGF-responsive growth and motility, a known signal to bypass androgen receptor dependence. Mutant delta-catenin promoted Myc-induced prostate tumorigenesis while increasing bFGF-p38 MAP kinase signaling, beta-catenin-HIF-1alpha expression, and the nuclear size. Therefore, intratumor delta-catenin heterogeneity originated from genetic remodeling promotes prostate cancer expansion towards androgen independent signaling, supporting a neomorphism model paradigm for targeting tumor progression. |
