IL13RA2 and brain metastasis
Despite the substantial progress in defining general mechanisms by which cancer cells in solid tumors acquire the hallmark capability to metastasize, the extent to which phenotypic plasticity at metastatic sites contributes to metastatic progression remains poorly understood. Brain metastatic colonization requires circulating tumor cells to be arrested at brain capillaries, extravasate into the brain parenchyma, survive antitumorigenic effects of brain immune surveillance cells, and colonize the brain by growing around existing vessels and adapting to the unique brain microenvironment. The transition between highly invasive phenotypes (for extravasation) to proliferative phenotype (for outgrowth) remains poorly understood.
IL-13 and Phenotypic Adaptation
We have recently shown that IL-13 Receptor alpha 2 (IL13RA2), a monomeric receptor with high affinity for IL13, is essential for cancer-cell survival, promoting proliferation while repressing invasion, and may play a role in phenotypic adaptation required for outgrowth of breast cancer cells in the brain. IL13Rα2 KD resulted in FAK downregulation, repression of cell cycle and proliferation mediators, and upregulation of Ephrin B1 signaling. Ephrin-B1 (i) promoted invasion of BC cells in vitro, (ii) marked micrometastasis and invasive fronts in BCBM, and (iii) predicted shorter disease-free survival and BM-free survival (BMFS) in breast primary tumors known to metastasize to the brain. In experimental metastases models, which bypass early tumor invasion, downregulation of IL13Rα2 before or after tumor seeding and brain intravasation decreased BMs, suggesting that IL13Rα2 and the promotion of a proliferative phenotype is critical to BM progression.
IL13Rα2 and the promotion of a proliferative phenotype is critical to BM progression
Funded by DoD Level I Breakthrough Award & Cancer League of Colorado (to DMC)
Dr. Cittelly featured on the University of Colorado Cancer Center website.