The Hippo pathway in immunity and cancer
Embargo Date
2021-01-30
OA Version
Citation
Abstract
The Hippo pathway integrates numerous stimuli into intracellular signaling that informs the cell of its structural features (actin cytoskeleton, polarity, cell shape), location, and surroundings (cell-cell contacts, growth factors, extracellular matrix), instructing cellular survival, proliferation, differentiation and fate. Dysregulated Hippo signaling leads to cell fate and developmental defects, and promotes tumorigenesis. We investigated the role of Hippo pathway transcriptional regulators YAP and TAZ (YAP/TAZ) in cancer metabolic reprograming and showed that they regulate the expression of glutamine transaminases that promote glutamine dependence in breast cancer cells. In breast cancer patients, YAP/TAZ activity positively correlates with transaminase expression, identifying transamination as a prospective clinical target in breast cancers driven by aberrant YAP/TAZ function. Critical regulators of cancer progression in the tumor microenvironment (TME) are T cells, whose activation and differentiation relies on signals regulated by the Hippo pathway in other contexts. We studied the effect of T cell specific YAP deficiency in anti-tumor T cell mediated immunity, which led us in identifying YAP as a suppressor of T cell activation and function. YAP deficiency enhanced CD4+ T cell differentiation to polarized subtypes. In in vivo mouse tumor models, YAP deficiency reduces tumor growth and augments the ability of CD8+ T cells to infiltrate tumors. Tumor infiltrating lymphocyte RNA-Seq identified YAP as a global suppressor of T cell responses in the TME and as a key negative regulator of T cell tumor infiltration and patient survival in many human cancers. Given these newly discovered effects of YAP in T cell biology, we further studied how YAP/TAZ deficiency affects the hallmark of adaptive immunity, T cell memory, during bacterial and viral infection and found that YAP/TAZ inhibit memory T cell generation. Lastly, we investigated the role of Hippo pathway kinases and YAP/TAZ inhibitors LATS1 and LATS2 in T cells and found that in contrast to YAP/TAZ they are indispensable for normal thymocyte development and function. Through this work, we define novel and critical roles of Hippo pathway signaling in T cell development and function, as well as cancer metabolic reprograming and propose T cell specific YAP inhibition for improving immune mediated cancer treatment.
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License
Attribution-NonCommercial-NoDerivatives 4.0 International