Recent advances in cancer biology have evolved to consider cancers as complex “rough” organs in which transformed cells along with other cell and non-cell constituents in the tumor microenvironment (TME) conspire to facilitate tumor growth and metastasis. With the increasing knowledge on the roles of TME in tumor formation and progression, the focus of cancer treatment has extended from targeting tumor cell itself to the TME. A full understanding of the signaling mechanisms mediating the communication between tumor cells and TME would be valuable for designing new and effective anti-cancer regimens. PML is a pleiotropic tumor suppressor, but its role in TME regulation is poorly characterized. In this study, we identify a PML ubiquitination pathway that is mediated by WDR4-containing Cullin4 ubiquitin ligase. Clinically, this PML degradation pathway is hyperactivated in lung cancer and correlates with poor prognosis. The WDR4/PML axis induces a set of cell surface or secreted proteins which elicit paracrine effects to stimulate migration, invasion, and metastasis. One of these proteins, CD73, additionally promotes an immunosuppressive TME by elevating intratumoral Tregs and M2 macrophages and reducing CD8+ T cells, as CD73 blockade reverses all of these effects of the WDR4/PML axis. Our study identifies WDR4 as an oncoprotein that negatively regulates PML to promote lung cancer progression by fostering an immunosuppressive and prometastatic TME, suggesting the potential of immune-modulatory approaches for treating tumors with aberrant PML degradation.
This paper is published in The Journal of Clinical Investigation on Aug 1 and is selected by the Editor as a highlight in the JCI This Month.
The full research article entitled “Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment” is available at The Journal of Clinical Investigation website at: https://www.jci.org/articles/view/89957
Authors : Ya-Ting Wang, Jocelyn Chen, Chou-Wei Chang, Jayu Jen, Tzu-Yu Huang, Chun-Ming Chen, Roger Shen, Suh-Yuen Liang, I-Cheng Cheng, Shuenn-Chen Yang, Wu-Wei Lai, Kuang-Hung Cheng, Tao-Shih Hsieh, Ming-Zong Lai, Hung-Chi Cheng, Yi-Ching Wang, Ruey-Hwa Chen
Updated : 2017.08.21