The Role of PTEN Loss in Tumor Maintenance Is Context Dependent

Inactivation of the tumor suppressor PTEN is a common feature of many human cancers, including T-cell acute lymphoblastic leukemia (T-ALL), and results in hyperactivation of PI3K/AKT signaling that stimulates tumor growth. However, the contribution of sustained PTEN loss to tumor maintenance and progression remains unclear. To address this question, Miething and colleagues generated a transgenic mouse model in which PTEN expression was reversibly suppressed via tetracycline-regulated expression of shRNA in lymphoid cells. Inactivation of PTEN in these mice induced the development of highly malignant CD4⁺CD8⁺ T-ALL that recapitulated several genetic features of human PTEN-mutated T-ALL and was associated with leukemic cell infiltration into the spleen, lymph nodes, liver, and intestine. Reactivation of PTEN expression prolonged the survival of leukemia-bearing mice, suggesting that continued PTEN inactivation may be required for tumor maintenance. Intriguingly, PTEN reactivation did not affect tumor burden in the spleen or lymph nodes, but instead selectively promoted apoptosis of disseminated leukemic cells in the intestine, indicating that the role of PTEN loss in tumor progression is dependent on the tumor microenvironment. Consistent with this finding, PTEN reactivation impaired PI3K/AKT activity in leukemic cells infiltrating the intestine but not the spleen. The tissue-specific effect of PTEN loss on disseminated tumor cell survival and homing was mediated by amplification of chemokine (C-C motif) ligand 25 (CCL25) signaling through its G-protein–coupled receptor (GPCR) CCR9 expressed on leukemic cells; in the absence of PTEN, CCL25 enhanced T-ALL cell migration, whereas inhibition of CCR9 specifically decreased leukemic cell dissemination in the intestine. These results identify a context-dependent interaction between PTEN loss and GPCR signaling in the tumor microenvironment that regulates tumor maintenance and generates intratumoral heterogeneity.

Miething C, Scuoppo C, Bosbach B, Appelmann I, Nakitandwe J, Ma J, et al. PTEN action in leukaemia dictated by the tissue microenvironment. Nature 2014 May 4 [Epub ahead of print].