Defining Early Escape Strategies in LKB1 Mutant Lung Cancer S1

 描述(申请人提供)：肺腺癌中第三个最常见的突变基因是激酶LKB1(STK11)，大约有25,000名患者有这种突变。与单独突变的患者相比，LKB1和KRAS共同突变的患者总存活率显著缩短，并且没有有效的靶向治疗。在基因工程Kras小鼠模型中，Lkb1的共突变足以促进肺腺癌的转移，原发肿瘤和转移瘤表现出EMT和黏附信号的异常激活。与这些数据一致，我们发表了三份报告，LKB1调节肺癌的运动，当存在时，限制关键的黏附信号分子，粘着斑激酶(FAK)的活性。此外，我们的初步数据显示，Lkb1缺陷的肿瘤细胞在体内以集体包的形式侵袭，在这样做的过程中，重塑了肿瘤微环境的胶原ECM，这一现象依赖于体外FAK的活性。这些来自小鼠模型的转移性肿瘤在原发肿瘤的集体侵袭包中显示异常的FAK激活。因此，我们假设LKB1突变细胞最初使用EMT通过基底膜侵袭，随后是基于FAK的有缺陷的黏附信号，允许细胞在转移过程中导航胶原微环境。为了测试这一点，我们将采用结合果蝇和小鼠遗传学力量的多模型方法，以及我们的大型临床注释人肺腺癌肿瘤库，以i)测试Lkb1突变细胞穿越基底膜所使用的机制和信号通路，ii)确定黏附信号改变是否通过胶原重塑在体内驱动细胞逃逸，以及iii)确定LKB1基因突变的人肺腺癌是否表现出与胶原重塑相关的黏附信号改变，并预测不良预后。我们认为，这种综合的方法可以克服传统体外系统的缺点，并解决我们的目标，即定义肺癌患者LKB1突变的生物学后果。

 DESCRIPTION (provided by applicant): The 3rd most commonly mutated gene in lung adenocarcinoma is the kinase LKB1 (STK11), where ~25,000 patients have this mutation. Patients that are co-mutated for LKB1 and KRAS have significantly shorter overall survival compared to either mutation alone and have no effective targeted therapies. In a genetically engineered Kras mouse model, co-mutation of Lkb1 is sufficient to promote metastasis of lung adenocarcinoma, and primary tumors and metastases show aberrant activation of both EMT and adhesion signaling. In agreement with these data, we have published three reports that LKB1 regulates lung cancer motility and when present, restrict the activity of a key adhesion signaling molecule, focal adhesion kinase (FAK). Moreover, our preliminary data show that Lkb1-deficient tumor cells invade as a collective pack in vivo, and in doing so, remodel the collagen ECM of the tumor microenvironment, a phenomenon that is dependent on the activity of FAK in vitro. These metastatic tumors from the mouse model show aberrant FAK activation within collective invasion packs of the primary tumors. Therefore, we hypothesize that LKB1-mutant cells use EMT to initially invade through the basement membrane, which is followed by defective FAK-based adhesion signaling that allows cells to navigate the collagen microenvironment during metastasis. To test this, we will take a multi-model approach that combines the power of Drosophila and mouse genetics, and our large clinically annotated human lung adenocarcinoma tumor bank to i) test the mechanism and signaling pathway used by Lkb1-mutant cells to traverse the basement membrane, ii) determine whether altered adhesion signaling drives in vivo cell escape through collagen remodeling, and iii) determine whether LKB1-mutant human lung adenocarcinoma exhibits altered adhesion signaling that correlates with collagen remodeling and predicts poor outcome. We propose that this comprehensive approach can overcome the shortcomings of traditional in vitro systems and address our goal of defining the biological consequences of LKB1 mutations in lung cancer patients.