WNT5a/ROR2-Mediated Hippo Pathway Activation in Prostate Cancer

去雄激素仍然是已经扩散的前列腺癌(PCA)的标准全身治疗方法 在前列腺癌之外，但大多数患者进展为转移性去势抵抗前列腺癌(MCRPC)。 其中许多肿瘤对阿比特龙或第二代AR拮抗剂有反应，但耐药 不可避免地会发展。在这个阶段，一些患者可能对紫杉烷或PARP抑制剂有反应，但治疗方案 大多数患者是有限的。Wnt信号的增加是被牵连的机制之一 在对ASI耐药的过程中。当Wnt配体结合时，典型的Wnt/β-连环蛋白途径被启动 与Frizzled型家族受体结合，从而导致β-连环蛋白的增加和TCF族转录的共激活 各种因素。WNTs的一个子集可以通过受体优先激活非规范的WNTs通路，包括 ROR1和ROR2。下游信号通路的定义不是很明确，而且依赖于上下文，但 包括平面细胞极性和Wnt-Ca++途径。值得注意的是，非规范的WNT信号也 据报道，抑制肿瘤抑制的河马途径，从而增强YAP1和核表达 Taz，随后刺激tead家族转录因子。WNT5A是主要的 非典型的Wnt在癌症中的表达经常是异常的，它与两种肿瘤都有关联- 抑制和促进肿瘤的活性。在前列腺癌中，Wnt5a表达增加与 MCRPC和神经内分泌PCa，但也与局限性PCa的预后较好有关， 并伴有生长抑制和休眠。虽然这些研究表明非规范的Wnt信号可以 既有抑制增长的作用，也有刺激作用，但调节这些影响的下游信号仍然存在 待定。我们发现Wnt5a在前列腺癌中的生长抑制作用是通过 ROR2，并且这个Wnt5a/ROR2信号正在激活河马途径，以抑制YAP1/TAZ的活性。 虽然Wnt信号与抑制河马途径有关，但我们的研究首次表明它可以 激活河马，为Wnt5a的生长抑制作用提供机制。我们假设这是 反映了ROR2的一项新功能，它依赖于上下文，并且可以识别将识别 对Wnt5a类似药物有反应的肿瘤亚群，如目前正在临床的Fox5 审判。这项提议的中心假设是，WNT5a模拟药物驱动非规范WNT 信号转导可以有效地治疗mCRPC(和其他实体肿瘤)的一部分，即它们的生长 抑制作用是通过激活河马途径实现的，这反映了生理上的负面影响 抑制YAP1/TAZ活性的反馈环。目标是确定WNT5a的分子基础- 介导河马通路的激活(目标1)，并评估刺激这一途径的治疗潜力 途径，包括识别可以预测哪些肿瘤可能对可用药有反应的生物标记物 WNT5A-模拟药物(目标2)。

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).