Defining Early Escape Strategies in LKB1 Mutant Lung Cancer S1

 描述（由申请人提供）：肺腺癌中第三大最常见的突变基因是激酶LKB 1（STK 11），约25，000例患者存在该突变。与单独的突变相比，LKB1和KRAS共突变的患者的总生存期显著缩短，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，并且原发性肿瘤和转移显示EMT和粘附信号传导的异常激活。与这些数据一致，我们已经发表了三篇报告，LKB 1调节肺癌运动，当存在时，限制关键粘附信号分子，粘着斑激酶（FAK）的活性。此外，我们的初步数据表明，Lkb1缺陷型肿瘤细胞在体内作为一个集体包侵入，并在这样做时，重塑肿瘤微环境的胶原ECM，这是一种依赖于体外FAK活性的现象。这些来自小鼠模型的转移性肿瘤在原发性肿瘤的集体侵袭包内显示异常的FAK活化。因此，我们假设LKB1突变细胞使用EMT最初通过基底膜侵入，随后是基于FAK的粘附信号传导缺陷，使细胞在转移过程中导航胶原微环境。为了测试这一点，我们将采取多模型方法，结合果蝇和小鼠遗传学的力量，以及我们的大型临床注释的人肺腺癌肿瘤库，以i）测试Lkb1突变细胞穿过基底膜所使用的机制和信号通路，ii）确定改变的粘附信号是否通过胶原重塑驱动体内细胞逃逸，和iii）确定LKB 1突变型人肺腺癌是否表现出与胶原重塑相关的改变的粘附信号传导并预测不良结果。我们认为，这种综合方法可以克服传统体外系统的缺点，并解决我们的目标，即确定肺癌患者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.