Defining the role of Wnt5a in LKB1-deficient non-small cell lung cancer metastasis

 描述（由申请人提供）：癌症的转移性传播和生长是几乎90%的癌症相关死亡的原因。目前使用标准疗法治疗转移性病变的能力极其有限，因为它们通常不可手术并且对化疗具有抗性。因此，了解这一过程的驱动因素并确定靶向转移性疾病的新方法至关重要。黑色素瘤和肺癌模型中的几条证据表明，LKB 1缺陷是转移的强促进剂，但LKB 1缺失促进肺肿瘤转移的机制尚未得到很好的定义。我们的初步数据表明，Wnt5a在LKB1缺陷的情况下上调，并考虑到其在其他癌症的侵袭和转移中的作用，以及在转移性人肺癌中的表达升高，Wnt5a可能是LKB1依赖性转移的下游介导物，并代表了这种疾病的有希望的治疗靶点。在这项提案中，Wnt5a在LKB 1缺陷型肺癌转移中的作用将在体外和体内以及靶向Wnt5a治疗NSCLC的治疗益处中得到解决。首先，基因缺失和病毒介导的过表达将用于评估Wnt5a对体外侵袭和转移表型的贡献，以及解决LKB 1对Wnt5a的依赖性以促进转移。Wnt5a调节对NSCLC细胞体内转移能力的影响将使用CRISPR技术在基因工程改造的NSCLC鼠模型中使用原位同种异体移植物移植和内源性缺失来解决。设计另外的研究以测试Wnt5a拮抗剂在体内抑制肿瘤生长和转移的治疗功效。最后，在这项研究中提出的实验将阐明Wnt5a下游激活的信号通路，这是转移的关键，通过评估已知的Wnt5a信号组分和RNA测序，以确定新的下游调节转移。总之，这些研究将确定Wnt5a在LKB1缺陷转移中的作用，并解决靶向Wnt5a信号传导在NSCLC转移中的治疗益处，以及在携带LKB1突变的肿瘤患者中增强疗效的潜力。

 DESCRIPTION (provided by applicant): Metastatic dissemination and outgrowth of cancers is responsible for almost 90% of cancer-related deaths. The current ability to treat metastatic lesions using standard therapy is extremely limited, as they are often inoperable and resistant to chemotherapies. Understanding of the drivers of this process and identifying novel ways to target metastatic disease is therefore of critical importance. Several lines of evidence in melanoma and lung cancer models suggest that LKB1-deficiency is a strong promoter of metastasis, but the mechanisms by which LKB1 loss promotes lung tumor metastasis have not been well defined. Our preliminary data suggest that Wnt5a is upregulated in LKB1-deficient contexts and given its role in invasion and metastasis in other cancers, as well as elevated expression in metastatic human lung cancer, it is possible that Wnt5a is a downstream mediator of LKB1 dependent metastasis and represents a promising therapeutic target for this disease. In this proposal, the role of Wnt5a in LKB1-deficient lung cancer metastasis will be addressed both in vitro and in vivo as well as their therapeutic benefits of targeting Wnt5a for treatment of NSCLC. First, both genetic deletion and viral-mediated overexpression will be used to evaluate the contribution of Wnt5a to invasion and metastatic phenotypes in vitro, as well as address the LKB1-dependency on Wnt5a to promote metastasis. The consequences of Wnt5a modulation on the ability of NSCLC cells to metastasize in vivo will be addressed using orthotopic allograft transplants and endogenous deletion in genetically engineered murine models of NSCLC using CRISPR technology. Additional studies are designed to test the therapeutic efficacy of Wnt5a antagonists to inhibit tumor growth and metastasis in vivo. Lastly, the experiments proposed in this fellowship will elucidate the signaling pathways activated downstream of Wnt5a that are critical for metastasis, both through evaluation of known Wnt5a signaling components and RNA sequencing to identify novel downstream regulators of metastasis. Together, these studies will define the role of Wnt5a in LKB1-deficient metastasis and address the therapeutic benefit of targeting Wnt5a signaling in NSCLC metastasis, with the potential for enhanced efficacy in patients with tumors harboring LKB1 mutations.