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

研究细胞外基质在转移和化疗耐药中的作用

基本信息

批准号：
9330827
负责人：
Madeleine Julie Oudin
金额：
$ 12.46万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330827
关键词：
Abdomen Affect Automobile Driving Behavior Biological Assay Biological Markers Cancer Patient Cause of Death Cell Proliferation Cell Survival Cells Cellular biology Cessation of life Chemotaxis Chemotherapy-Oncologic Procedure Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Collagen Collection Communities Complement Complex Cues Data Disease Distant Drug resistance EGF gene Engineering Ensure Environment Extracellular Matrix Fibronectins Funding Genes Glycoproteins Goals Growth Factor Image In Vitro Institutes Invaded Investigation Knock-out Link Malignant Neoplasms Mentors Metastatic Neoplasm to the Liver Metastatic breast cancer Methods Modeling Morphology Needles Neoplasm Metastasis Out-Migrations Pathway interactions Patients Pharmaceutical Preparations Play Primary Neoplasm Process Proteins Proteoglycan Relapse Research Resistance Resistance development Role Scaffolding Protein Science Shapes Signal Pathway Signal Transduction Signal Transduction Pathway Site Stromal Cells Structure System Systems Biology Tissues Training Training Programs Tumor Cell Migration Universities Work Xenograft procedure career development cell growth cell motility chemotherapy clinical effect clinically relevant implantable device in vitro Assay in vivo in vivo Model interdisciplinary approach intravital imaging meetings member mouse model neoplastic cell novel outreach prevent resistance mechanism response standard of care student mentoring triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression

项目摘要

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.

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，化疗仍然是护理标准。化疗的好处对于转移性疾病的治疗已经有很好的记录，超过50%的三阴性乳腺癌病人对化疗产生了抗药性。提高我们对推动转移和耐药性将有助于确定可用于预测它们的生物标志物，有针对性的信号通路，可以用来防止他们。现在很清楚的是肿瘤微环境可能有助于肿瘤进展和转移。细胞外基质（ECM）形成一个为肿瘤细胞提供结构和信号的蛋白质的复杂支架。然而，其在其如何驱动侵袭和转移以及如何影响对化疗的反应仍然未被探索。本提案的主要目标是研究ECM在转移和化疗耐药性中的作用，一种跨学科的方法，将联合收割机细胞生物学，活体成像，系统生物学和植入式装置.首先，我们已经证明了纤维连接蛋白的梯度可以促进肿瘤细胞的定向运动，对转移很重要。当高转移性肿瘤细胞受到EGF和当它们同时与纤维连接蛋白结合时，它们将比单独使用每种线索时侵入更多。目标1的目标是研究ECM与生长因子在局部侵袭和转移中的作用，殖民化第二，初步探讨化疗药物对高侵袭性肺癌的影响。肿瘤细胞显示，它们对细胞增殖和迁移具有不同的作用，调节ECM灵敏度和组织。在目标2中，我将确定影响细胞生长的ECM组合， CRISPR基因敲除筛选， ECM调节蛋白，以确定新的基因调节化学敏感性。我还提出了一个广泛的培训计划，以支持我向独立过渡。研究麻省理工学院科赫研究所提供的环境是杰出的，并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。我有组建了一个特殊的团队来帮助我实现我的目标：弗兰克·格特勒教授，细胞运动专家，教授耐药机制研究专家Michael Hemann将成为我的导师。Richard教授海恩斯是ECM研究的先驱，道格·劳芬伯格教授是癌症系统生物学的领导者，我的导师委员会的成员。我的培训也包括指导学生，参加并在会议上介绍我的工作，成为ECM和癌症的积极成员社区和科学推广。拟议的研究和职业发展培训将共同确保我实现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。