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

摘要 整合素在癌症进展中起多方面的作用，通过调节细胞迁移以及 介导在增殖和化学抗性中重要的信号传导途径。我们的实验室是第一个 证明白血病细胞利用神经干细胞迁移途径侵入中枢神经系统， 通过沿着穿过骨髓的血管的近腔表面迁移， 和软脑膜（LM）。我们发现这一过程是由白血病细胞整合素α6介导的， 接合这些血管周围的基底膜中的层粘连蛋白。与白血病相似，乳腺癌 癌症转移到LM导致严重的发病率，并且是迅速致命的并发症。我 初步数据表明，乳腺癌细胞利用α6和α3整联蛋白-层粘连蛋白相互作用， 入侵登月舱我还观察到，接种在层粘连蛋白上的乳腺癌细胞表现出对 化疗阿霉素。整合素α6 KO对化疗不敏感， 假设整合素α3通过激活化学保护信号而发挥多方面的作用 层粘连蛋白接合的通路。在这项研究补助金中，我建议更全面地定义以下方面的作用： α3整合素-层粘连蛋白相互作用对三阴性乳腺癌LM转移的调控作用 导血管和促进转移微环境中的化学抗性。

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.