Defining mechanisms of cancer chemoresistance and metastasis

定义癌症化疗耐药和转移的机制

• 批准号: 8860124
• 负责人: Swarnali Acharyya
• 金额: $ 24.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8860124
• 关键词: 4q21; Address; Adenocarcinoma; Advanced Malignant Neoplasm; Affect; Animal Model; Applications Grants; Area; Award; Biological; Biological Assay; Biology; Blood; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast cancer metastasis; CXCL1 gene; Calculi; Cancer Patient; Cell Survival; Cells; Cellular biology; Clinic; Clinical; Clinical Management; Communities; Complement; Cytotoxic Chemotherapy; Data; Disease; Drug resistance; Endothelial Cells; Environment; Failure; Fibroblasts; Gene Components; Genotoxic Stress; Goals; Hospitals; Human; ITGAM gene; Immune; Inflammatory; Invaded; Investigation; Kinetics; Knowledge; Laboratories; Lead; Light; Link; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Metastatic Lesion; Mining; Mission; Modeling; Morbidity - disease rate; Myeloid Cells; Neoadjuvant Therapy; Neoplasm Metastasis; Organ; Paracrine Communication; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Quality of life; Research; Research Institute; Research Personnel; Residual state; Resistance; Resources; Role; S100A8 gene; Sampling; Site; Smooth Muscle Myocytes; Source; Stress; Structure of parenchyma of lung; TNF gene; Testing; Therapeutic; Time; Tissues; Training; Universities; Work; abstracting; anticancer research; base; bone; cancer cell; cancer type; career; cell type; chemokine; chemotherapy; clinically relevant; cytokine; design; drug development; improved; in vivo; inhibitor/antagonist; innovation; insight; interest; malignant breast neoplasm; medical schools; mortality; neoplastic cell; novel; overexpression; paracrine; post-doctoral training; preclinical study; prevent; programs; resistance mechanism; response; small molecule; standard of care; therapy resistant; tumor; tumor microenvironment

Abstract: My long-term career goal is to contribute to cancer research as an independent investigator that will lead to better ways of treating cancer. It is well known that 90% of cancer patients die because of metastasis, which results in the spreading of tumor cells to different organs such as lung and bone. As an important step towards achieving my career goal, I joined the laboratory of Dr. Joan Massague, one of the leaders in breast cancer metastasis field for my postdoctoral training. Located in the world's premier cancer research institutes, Memorial Sloan Kettering Cancer Center, this research environment provides unparalleled resources and expertise from clinicians and basic researchers. Innovative research at MSKCC is encouraged and is complemented with inputs from the tri-institutional community comprising of Rockefeller University, Weill-Cornell Medical College and clinical input from investigators from the Memorial Hospital. My work in Dr. Massague's laboratory sheds light on how the tumor microenvironment responds to chemotherapy to benefit cancer cell survival. Our evidence from animal models and clinical samples suggest that chemotherapy induces a burst of cytokines including TNF-¿ from several components of the tumor microenvironment such as endothelial and smooth muscle cells. An undesirable consequence of the stromal TNF-¿ is to boost CXCL1/2 expression in breast cancer cells. A higher level of CXCL1/2 then drives the paracrine loop involving myeloid cell-derived S100A8/9 to enhance cancer cell survival. An adverse cycle involving TNF-¿-CXCL1/2- S100A8/9 could thus be expanded in response to chemotherapy. Once initiated, this chemo- protective program could become self-sustaining, leading to the enrichment of residual aggressive clones able to resist chemotherapy and thrive in the lung parenchyma and elsewhere. Obtaining a transitional award would be an ideal stepping-stone to independence with a mentored and independent phase. Based on our previous findings, my research plan critically addresses the role of the TNF-¿-CXCL1/2-S100A8/9 axis in chemoresistance and metastasis in two different cancer types, breast and lung cancer. In the case of breast cancer proposed for the K99 phase, based on our work I will interrogate the link between chemotherapy, kinetics and biology of myeloid cell recruitment and metastasis progression in breast cancer models. The second aim will focus on devising ways of targeting the TNF-¿-CXCL1/2-S100A8/9 axis most effectively. During this time, I will gain training in the area of lung cancer and familiarize myself with lung cancer metastasis models. In my independent phase, I will continue to focus on the components of the TNF-¿-CXCL1/2-S100A8/9 axis (GOIs) that are activated with chemotherapy or during metastasis. In Aim 4, I will dissect the functional contribution of the GOIs in mediating chemoresistance linked metastasis.

抽象的： 我的长期职业目标是作为独立研究者为癌症研究做出贡献， 将导致更好的治疗癌症方法。众所周知，有90％的癌症患者死亡 由于转移，这导致肿瘤细胞扩散到不同的器官，例如 肺和骨头。作为实现职业目标的重要一步，我加入了实验室 Joan Massague博士，我的博士后乳腺癌转移领域的领导者之一 训练。纪念斯隆·克特林（Memorial Sloan Kettering 癌症中心，该研究环境提供了无与伦比的资源和专业知识 临床医生和基础研究人员。鼓励MSKCC的创新研究 完成了三机构社区完成洛克菲勒的投入 大学，威尔 - 科内尔医学院和纪念馆的调查员的临床意见 医院。 我在Massague博士实验室的工作阐明了肿瘤微环境的反应 化学疗法使癌细胞存活有益。我们来自动物模型和临床的证据 样品表明化学疗法诱导了几种细胞因子，包括几种TNF- 肿瘤微环境的成分，例如内皮和平滑肌细胞。一个 基质TNF-的不良后果是促进乳腺癌中的CXCL1/2表达 细胞。然后，更高水平的CXCL1/2驱动旁分泌环涉及髓样细胞来源 S100A8/9可增强癌细胞的存活。涉及TNF-¿-CXCL1/2-的不利周期 因此，S100A8/9可以响应化学疗法而扩展。一旦开始，这种化学 保护计划可能会变得自我维持，导致残留物丰富 侵略性克隆可以抵抗化学疗法并在肺实质中繁殖 别处。 获得过渡性奖励将是与 指导和独立阶段。根据我们以前的发现，我的研究计划批判性 探讨TNF-�-CXCL1/2-S100A8/9轴在化学上和转移中的作用 两种不同的癌症类型，乳腺癌和肺癌。就乳腺癌提议 K99阶段，根据我们的工作，我将询问化学疗法，动力学和 乳腺癌模型中髓样细胞募集和转移进展的生物学。这 第二个目标将重点放在设计目标tnf-¿-cxcl1/2-s100a8/9轴的方法上 有效地。在此期间，我将接受肺癌领域的培训，并熟悉自己 与肺癌转移模型。在我的独立阶段，我将继续专注于 TNF-¿ 或转移期间。在AIM 4中，我将剖析Gois的功能贡献 化学抗性连接转移。