Defining mechanisms of cancer chemoresistance and metastasis

描述（由申请人提供）：我的长期职业目标是作为一名独立研究者为癌症研究做出贡献，这将带来更好的治疗癌症的方法。众所周知，90%的癌症患者死于转移，这导致肿瘤细胞扩散到不同的器官，如肺和骨。作为实现职业目标的重要一步，我加入了乳腺癌转移领域的领导者之一Joan Massague博士的实验室进行博士后培训。位于世界领先的癌症研究机构，纪念斯隆凯特琳癌症中心，这种研究环境提供了无与伦比的资源和专业知识，从临床医生和基础研究人员。MSKCC的创新研究受到鼓励，并得到了洛克菲勒大学，威尔康奈尔医学院和纪念医院研究人员临床投入组成的三机构社区的补充。 我在Massague博士实验室的工作揭示了肿瘤微环境如何对化疗做出反应，以利于癌细胞存活。我们从动物模型和临床样本中获得的证据表明，化疗诱导了肿瘤微环境中几种成分（如内皮细胞和平滑肌细胞）的细胞因子（包括TNF-α）爆发。基质TNF-α的一个不良后果是促进乳腺癌细胞中CXCL 1/2的表达。更高水平的CXCL 1/2然后驱动涉及骨髓细胞衍生的S100 A8/9的旁分泌环，以增强癌细胞存活。因此，涉及TNF-<$-CXCL 1/2-S100 A8/9的不良周期可能会因化疗而扩大。一旦启动，这种化学保护程序可以自我维持，导致能够抵抗化疗并在肺实质和其他地方茁壮成长的残留侵袭性克隆的富集。获得一个过渡奖将是一个理想的垫脚石，以指导和独立的阶段独立。基于我们以前的研究结果，我的研究计划重点讨论了TNF-<$-CXCL 1/2-S100 A8/9轴在两种不同癌症类型（乳腺癌和肺癌）的化疗耐药性和转移中的作用。在K99期乳腺癌的情况下，基于我们的工作，我将询问化疗，骨髓细胞募集的动力学和生物学与乳腺癌模型中的转移进展之间的联系。第二个目标将集中于设计最有效地靶向TNF-α-CXCL 1/2-S100 A8/9轴的方法。在此期间，我将获得肺癌领域的培训，并熟悉肺癌转移模型。在我的独立阶段，我将继续关注TNF-α CXCL 1/2-S100 A8/9轴（GOI）的组成部分，这些组成部分在化疗或转移过程中被激活。在目标4中，我将剖析GOIs在介导化疗耐药相关转移中的功能贡献。

DESCRIPTION (provided by applicant): 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 wel 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 chemoprotective 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-alpha-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-alphaCXCL1/2-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.