Investigating the role of the extracellular matrix in metastasis and chemo-resistance

项目摘要 转移，即原发肿瘤细胞的扩散，是癌症患者死亡的主要原因。 对于转移性乳腺癌，化疗仍然是治疗的标准。虽然化疗的好处 对于转移性疾病的治疗已经有了很好的文献记载，超过50%的三阴性乳腺癌 患者对化疗产生抗药性。增加我们对驱动机制的理解 转移和耐药性将有助于识别可以用来预测它们的生物标记物，并表征 有针对性的信号通路可以用来预防它们。现在人们很好地认识到，这种肿瘤 微环境可以促进肿瘤的进展和转移。细胞外基质(ECM)，形成 为肿瘤细胞提供结构和信号的蛋白质的复杂支架。然而，它在这方面的作用 推动肿瘤的侵袭和转移，以及它如何影响化疗的反应，目前尚不清楚。 这项建议的主要目标是研究ECM在转移和化疗耐药中的作用，使用 一种结合了细胞生物学、活体成像、系统生物学和植入性的跨学科方法 设备。首先，我们已经证明，梯度的纤维连接蛋白可以促进肿瘤细胞的定向运动，a 对转移很重要的过程。当高转移的肿瘤细胞受到EGF和 纤维连接蛋白的同时，它们会比单独使用每条线索侵袭得更多。目标1的目标是 研究细胞外基质与生长因子信号在局部侵袭和转移中的作用 殖民主义。二、化疗药物对高侵袭性肿瘤影响的初步探讨 肿瘤细胞显示，它们可以对细胞的增殖和迁移产生不同的影响，也可以 规范ECM敏感性和组织。在目标2中，我将确定影响细胞生长和 对临床相关化疗方案的反应并进行CRISPR基因敲除筛查 ECM调节蛋白以识别调节化疗敏感性的新基因。 我还提出了一个广泛的培训计划，以支持我向独立的过渡。这项研究 麻省理工学院科赫研究所提供的环境非常出色，提供了无与伦比的机会 科学讨论，生物学家和工程师之间的合作，以及职业发展。我有过 组建了一个出色的团队来帮助我实现目标：弗兰克·格特勒教授，细胞运动学专家，以及 研究耐药机制的专家迈克尔·赫曼教授将成为我的导师。理查德教授 ECM研究的先驱海恩斯和癌症系统生物学的领导者道格·劳芬伯格教授将成为 合作者和我的指导委员会的成员。我的培训还将包括指导学生， 出席并在会议上介绍我的工作，成为ECM和癌症的活跃成员 社区，以及科学外展。拟议的学习和职业发展培训将结合在一起 确保我实现了在一所重点大学建立一个成功的、独立资助的实验室的目标。

Project Summary Metastasis, the dissemination of cells from the primary tumor, is the leading cause of death in cancer patients. For metastatic breast cancer, chemotherapy remains the standard of care. While the benefits of chemotherapy for the treatment of metastatic disease have been well documented, over 50% of triple-negative breast cancer patients become resistant to chemotherapy. Increasing our understanding of the mechanisms driving metastasis and drug resistance will help identify biomarkers that can be used to predict them, and characterize targetable signaling pathways to that can be used to prevent them. It is now well appreciated that the tumor microenvironment can contribute to tumor progression and metastasis. The extracellular matrix (ECM), forms a complex scaffold of proteins that provides both structure and signals to the tumor cells. However, its role in driving invasion and metastasis and how it could affect response to chemotherapy remains unexplored. The main goal of this proposal is to investigate the role of the ECM in metastasis and chemo-resistance, using an interdisciplinary approach that will combine cell biology, intravital imaging, systems biology and implantable devices. First, we have shown that gradients of fibronectin can promote directional motility of tumor cells, a process important for metastasis. When highly metastatic tumor cells are subject to gradients of EGF and fibronectin simultaneously, they will invade even more than with each cue alone. The goal of Aim 1 is to investigate the contribution of ECM versus growth factor cues during local invasion and metastatic colonization. Second, preliminary investigation into the effect of chemotherapeutic drugs on highly invasive tumor cells revealed that they can have differential effects on cell proliferation and migration, and can also regulate ECM sensitivity and organization. In Aim 2, I will identify ECM combinations that affect cell growth and migration in response to clinically relevant chemotherapy regimens and perform a CRISPR knockout screen of ECM-regulator proteins to identify novel genes regulating chemo-sensitivity. I also propose an extensive training program that will support my transition to independence. The research environment provided by the Koch Institute at MIT is outstanding, and offers unequaled opportunities for scientific discussion, collaboration between biologists and engineers, and career development. I have assembled an exceptional team to help me achieve my goals: Prof. Frank Gertler, expert in cell motility, and Prof. Michael Hemann, expert in studying mechanisms of drug resistance will be my mentors. Prof. Richard Hynes, a pioneer in ECM research, and Prof. Doug Lauffenburger, leader in cancer systems biology, will be collaborators and members of my mentoring committee. My training will also involve mentoring students, attending and presenting my work at meetings to become an active member of the ECM and cancer communities, and science outreach. Together, the proposed studies and career development training will ensure I achieve my goal of establishing a successful, independently-funded lab at a major university.