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

 描述(申请人提供)：癌症的转移扩散和生长导致了近90%的癌症相关死亡。目前使用标准疗法治疗转移性病变的能力极其有限，因为它们往往无法手术，而且对化疗具有抵抗力。因此，了解这一过程的驱动因素并确定针对转移性疾病的新方法至关重要。在黑色素瘤和肺癌模型中的一些证据表明，LKB1缺失是转移的强烈促进因素，但LKB1缺失促进肺癌转移的机制尚未很好地确定。我们的初步数据表明，Wnt5a在LKB1缺乏的情况下上调，考虑到它在其他癌症的侵袭和转移中的作用，以及在转移性人类肺癌中的高表达，Wnt5a可能是LKB1依赖转移的下游介质，并有望成为该疾病的治疗靶点。在这项提案中，Wnt5a在体外和体内LKB1缺陷的肺癌转移中的作用以及它们靶向Wnt5a治疗非小细胞肺癌的疗效将被讨论。首先，基因缺失和病毒介导的过表达将被用来评估Wnt5a在体外侵袭和转移表型中的作用，以及解决LKB1依赖Wnt5a促进转移的问题。在使用CRISPR技术的NSCLC基因工程小鼠模型中，Wnt5a对NSCLC细胞体内转移能力的调节将通过原位同种异体移植和内源性缺失来解决。其他研究旨在测试Wnt5a拮抗剂在体内抑制肿瘤生长和转移的治疗效果。最后，本研究中提出的实验将通过评估已知的Wnt5a信号成分和RNA测序来确定新的转移下游调控因子，从而阐明激活Wnt5a下游的信号通路对转移至关重要。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信号在非小细胞肺癌转移中的治疗益处，并有可能提高携带LKB1突变的肿瘤患者的疗效。

 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.