Defining mechanisms of cancer chemoresistance and metastasis

摘要： 我的长期职业目标是作为一名独立的研究人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，例如 肺和骨头作为实现职业目标的重要一步，我加入了 博士Joan Massague，我博士后的乳腺癌转移领域的领导者之一， 训练位于世界上首屈一指的癌症研究机构，纪念斯隆凯特琳 癌症中心，这个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。MSKCC的创新研究受到鼓励， 辅以洛克菲勒等三大机构的投入 大学，威尔康奈尔医学院和临床输入的研究人员从纪念馆 医院 我在Massague博士实验室的工作揭示了肿瘤微环境如何反应 到化疗来帮助癌细胞存活。我们的证据来自动物模型和临床 样本表明，化疗诱导了包括TNF-α在内的细胞因子的爆发， 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TNF-α的不良后果是促进乳腺癌中CXCL 1/2的表达 细胞更高水平的CXCL 1/2然后驱动涉及骨髓细胞来源的旁分泌回路。 S100A8/9增强癌细胞存活。涉及TNF-α-CXCL1/2- 因此，S100A8/9可以响应于化疗而扩增。一旦开始，化疗- 保护计划可能会自我维持，导致残留物的富集。 能够抵抗化疗并在肺实质中茁壮成长的侵袭性克隆， 其他地方 获得一个过渡性裁决将是一个理想的垫脚石，以独立， 指导和独立阶段。基于我们以前的发现，我的研究计划批判性地 阐明了肿瘤坏死因子-<$-CXCL1/2-S100A8/9轴在肺癌化疗耐药性和转移中的作用， 两种不同的癌症，乳腺癌和肺癌在乳腺癌的情况下， K99阶段，基于我们的工作，我将询问化疗，动力学和 乳腺癌模型中骨髓细胞募集和转移进展的生物学。的 第二个目标将集中在设计靶向TNF-κ-CXCL1/2-S100A8/9轴的方法， 有效地在此期间，我将获得肺癌领域的培训， 肺癌转移模型。在我的独立阶段，我将继续专注于 化疗激活的TNF-<$-CXCL1/2-S100A8/9轴（GOI）组分 或在转移期间。在目标4中，我将剖析GOI在调解中的功能贡献， 化疗耐药相关的转移。

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.