WNT5a/ROR2-Mediated Hippo Pathway Activation in Prostate Cancer

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Androgen deprivation remains the standard systemic treatment for prostate cancer (PCa) that has spread beyond the prostate, but most patients progress to metastatic castration-resistant prostate cancer (mCRPC). Many of these tumors will respond to abiraterone or to second generation AR antagonists, but resistance inevitably develops. Some patients at this stage may respond to taxanes or to PARP inhibitors, but options for the majority of patients are limited. Increased Wnt signaling is one of the mechanisms that has been implicated in the progression to ASI resistance. The canonical Wnt/β-catenin pathway is initiated when a Wnt ligand binds to a Frizzled family receptor, which results in increased β-catenin and coactivation of TCF family transcription factors. A subset of Wnts can preferentially activate noncanonical Wnt pathways through receptors including ROR1 and ROR2. The downstream signaling pathways are less well-defined and are context dependent, but include the planar cell polarity and Wnt-Ca++ pathways. Notably, noncanonical Wnt signaling has also been reported to inhibit the tumor suppressive Hippo pathway, thereby enhancing the nuclear expression of YAP1 and TAZ, with subsequent stimulation of the TEAD-family transcription factors. Wnt5a is the predominant noncanonical Wnt whose expression is often dysregulated in cancer, and it has been implicated in both tumor- suppressive and tumor-promoting activities. In PCa, increased Wnt5a expression has been associated with mCRPC and with neuroendocrine PCa, but has also been associated with better prognosis in localized PCa, and with growth suppression and dormancy. While these studies indicate that noncanonical Wnt signaling can have growth suppressive as well as stimulatory effects, the downstream signals mediating these effects remain to be established. We have found that the growth suppressive effects of Wnt5a in PCa are mediated through ROR2, and that this Wnt5a/ROR2 signaling is activating the Hippo pathway to suppress YAP1/TAZ activity. While Wnt signaling has been linked to suppression of the Hippo pathway, our studies are the first to show it can activate Hippo and provide a mechanism for the growth suppressing effects of Wnt5a. We hypothesize this reflects a novel function of ROR2 that is context dependent, and that biomarkers can be identified that will identify the subset of tumors that will be responsive to Wnt5a-mimetic drugs such as Foxy5, which is currently in clinical trials. The central hypotheses of this proposal are that Wnt5a-mimetic drugs that drive noncanonical Wnt signaling can be an effective treatment for a subset of mCRPC (and other solid tumors), that their growth suppressive effects are through Hippo pathway activation, and that this reflects a physiological negative feedback loop to restrain YAP1/TAZ activity. The objectives are to determine the molecular basis for Wnt5a- mediated activation of the Hippo pathway (Aim 1) and to assess the therapeutic potential of stimulating this pathway, including the identification of biomarkers that can predict which tumors may respond to available Wnt5a-mimetic drugs (Aim 2).