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.

摘要： 我的长期职业目标是作为一名独立的调查员为癌症研究做出贡献 将带来更好的治疗癌症的方法。众所周知，90%的癌症患者死亡 由于转移，导致肿瘤细胞扩散到不同的器官，如 肺和骨头。作为实现职业目标的重要一步，我加入了 琼·马萨格博士，我的博士后在乳腺癌转移领域的领导者之一 训练。斯隆·凯特林纪念医院位于世界一流的癌症研究机构 癌症中心，这一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。鼓励和支持MSKCC的创新研究 与洛克菲勒三机构社区的投入相辅相成 大学，威尔-康奈尔医学院和来自纪念馆的研究人员的临床投入 医院。 我在马萨格博士实验室的工作揭示了肿瘤微环境是如何反应的 到化疗，以利于癌细胞存活。我们来自动物模型和临床的证据 样本表明，化疗诱导了包括肿瘤坏死因子在内的几种细胞因子的暴发 肿瘤微环境的组成部分，如内皮细胞和平滑肌细胞。一个 间质肿瘤坏死因子的不良后果是促进乳腺癌中CXCL1/2的表达 细胞。然后，较高水平的CXCL1/2驱动旁分泌环路，涉及髓系细胞来源 S100A8/9提高癌细胞存活率。涉及肿瘤坏死因子-β-CXCL1/2-的不良循环- 因此，S100A8/9可以扩增以响应化疗。一旦启动，这种化疗- 保护计划可能会自我维持，导致残留物的浓缩 侵袭性克隆能够抵抗化疗并在肺实质和 其他地方。 获得过渡性奖项将是获得独立的理想踏脚石 指导和独立阶段。基于我们之前的发现，我的研究计划 探讨肿瘤坏死因子-β-CXCL1/2-S100A8/9轴在肺癌化疗耐药和转移中的作用 两种不同的癌症，乳腺癌和肺癌。在建议治疗乳腺癌的情况下 K99阶段，基于我们的工作，我将询问化疗、动力学和 乳腺癌模型中髓系细胞募集和转移进展的生物学。这个 第二个目标将集中在设计针对肿瘤坏死因子-？-CXCL1/2-S100A8/9轴的方法 有效地。在这段时间里，我将接受肺癌领域的培训，熟悉自己 建立了肺癌转移模型。在我的独立阶段，我将继续专注于 化疗激活的肿瘤坏死因子-β-CXCL1/2-S100A8/9轴(GOI)的组成 或在转移过程中。在目标4中，我将剖析政府当局在调解中的职能贡献 化疗耐药与转移有关。