A DUAL ROLE OF INTEGRIN ALPHA-3 IN BREAST CANCER CNS METASTASIS & CHEMORESISTANCE

摘要 整合素通过调节细胞迁移以及在癌症进展中发挥多方面的作用 介导在细胞增殖和化疗耐药中起重要作用的信号通路。我们的实验室是第一个 证明白血病细胞使用神经干细胞迁移途径侵袭中枢神经 中枢神经系统(CNS)沿横穿骨髓的血管的腔面迁移 和Leptomeninges(Lm)。我们发现这一过程是由白血病细胞整合素α6介导的。 将层粘连蛋白结合在这些血管周围的基底膜上。类似于白血病，乳房 肿瘤转移到肺大动脉会导致严重的并发症，是一种迅速致命的并发症。我的 初步数据表明，乳腺癌细胞利用α6和α3整合素-层粘连蛋白相互作用来 入侵登陆舱。我还观察到，层粘连蛋白上的乳腺癌细胞对 化疗药物阿霉素。整合素α6 KO不会使细胞对化疗敏感 假设整合素α3通过激活化学保护信号发挥多方面的作用 层粘连蛋白接合的途径。在这项研究拨款中，我建议更全面地界定 α-3整合素-层粘连蛋白相互作用对三阴性乳腺癌转移的调控作用 在转移性微环境中促进化疗耐药。

ABSTRACT Integrins serve a multifaceted role in cancer progression by regulating cell migration as well as mediating signaling pathways important in proliferation and chemoresistance. Our lab was the first to demonstrate that leukemia cells use a neural stem cell migratory pathway to invade the central nervous system (CNS) by migrating along the abluminal surface of blood vessels that traverse the bone marrow and leptomeninges (LM). We showed that this process was mediated by leukemia cell integrin α6 engaging laminin in the basement membrane surrounding these vessels. Similar to leukemia, breast cancer metastasis to the LM results in severe morbidity and is a rapidly fatal complication. My preliminary data suggest that breast cancer cells utilize both α6 and α3 integrin-laminin interactions to invade the LM. I have also observed that breast cancer cells plated on laminin exhibit resistance to the chemotherapeutic doxorubicin. Integrin α6 KO does not sensitize the cells to chemotherapy leading me to hypothesize that integrin α3 serves a multifaceted role by activating chemoprotective signaling pathways upon laminin engagement. In this research grant, I propose to more fully define the role of α3 integrin-laminin interactions in regulating triple negative breast cancer LM metastasis along emissary vessels and in promoting chemoresistance in the metastatic microenvironment.