Defining a Stromal Signature that Facilitates Progression of Lethal Cancers

定义促进致命癌症进展的基质特征

• 批准号: 10469340
• 负责人: PHILIPPE GASCARD
• 金额: $ 24.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469340
• 关键词: Award; Benchmarking; Breast; Camellia sinensis; Cells; Cellular biology; Characteristics; Deposition; Desmoplastic; Diagnosis; Disease; Down-Regulation; Drug resistance; Environment; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Extracellular Matrix; Fibroblasts; Funding; Generations; Goals; Hypoxia; Immune response; Immunohistochemistry; In Vitro; Instruction; Laboratories; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mesenchymal; Metaplasia; Metaplastic Carcinoma; Metaplastic carcinoma of the breast; Modeling; Mus; Outcome; Patients; Phenotype; Play; Positioning Attribute; Post-Translational Protein Processing; Property; Protein Biochemistry; Proteins; Proteomics; Recurrence; Regimen; Research; Role; Signal Pathway; Specialist; Specimen; Stress; Stromal Cells; Stromal Change; Testing; Therapeutic; Tissues; Up-Regulation; Veterinarians; Xenograft Model; breast tumorigenesis; cancer subtypes; cancer type; clinically relevant; comparative; data mining; design; experience; gene expression database; in vivo; insight; interest; macrophage; malignant breast neoplasm; mouse model; multidisciplinary; novel; programs; relapse risk; response; risk minimization; three dimensional cell culture; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

Project Summary/Abstract The activity proposed in this Research Specialist Award application is in line with the long-standing goals of Dr. Thea Tlsty (the Unit Director)'s currently NCI-funded research program which currently supports my activity/effort: i) understand dynamic mechanisms underlying cellular plasticity and tissue response to stress; and ii) explore the role of tissue microenvironment and how these multiple factors contribute to tumor initiation and progression. These efforts are particularly worthwhile when dealing with the most lethal type of breast cancer, metaplastic breast cancers (MBCs). Identifying tissue components and signaling pathways that contribute to the emergence of these cancers in order to design more successful therapies for patients diagnosed with MBCs is indeed of the outmost clinical relevance. This application is the result of my personal ‘twist’ on the long-term interest of the Tlsty laboratory on the role of stromal-epithelial interactions in breast tumorigenesis. Its core concept relies on the increasingly appreciated notion that cancer progression requires an instructive tumor microenvironment (TME). Generation of a TME results from: acquisition of a cancer- associated fibroblast signature, a shift in macrophage type, alterations of ECM characteristics that either facilitate or counteract tumor growth, a corrupted immune response, an expanded and leaky vasculature and as a correlate an hypoxic environment and increased epithelial cell plasticity. Such phenotypes are exemplified in aggressive tumors characterized by a desmoplastic stroma with extensive and altered ECM deposition typified by MBCs. Thus, the imbalance in ECM composition seen in MBCs is the result of extensive structural and functional stromal changes that result from alterations in both stromal and epithelial cell properties. Our provocative prediction that a specific ECM/stromal make-up may identify cancers with the poorest outcome across breast cancer subtypes (luminal, Her2-positive, basal-like) may be of high clinical relevance not only for MBCs and basal-like cancers, but also for luminal breast cancers with late recurrence. To gain valuable insights, I will: i) identify stromal drivers (and repressors) of progression of MBCs through comparative proteomic analysis of ECM from breast tumor (including MBC) and disease-free breast specimens with an emphasis on post-translational modification status; ii) interrogate gene expression databases for upregulation (or down-regulation) of these ECM proteins across breast cancer subtypes (luminal, Her2-positive, basal, claudin low) through data mining; iii) test the ability of some of these ECM proteins to drive (or repress) cell plasticity (multilineage commitment and epithelial mesenchymal transition) in vitro using 3D cell culture models; and iv) confirm in vivo the pro- (or anti-)metaplastic/tumorigenic activity of these ECM proteins in murine xenograft models. My extensive experience in protein biochemistry, cell biology and characterization of mouse models combined with my recent interest in data mining and multiplex immunohistochemistry, place me in an optimal position for the novel pursuit of ECM alterations underlying progression of MBCs.

项目总结/摘要 这项研究专家奖申请中提出的活动符合博士的长期目标。 Thea Tlsty（单位主任）目前的研究计划，目前支持我的 活动/努力：i）了解细胞可塑性和组织对压力反应的动力学机制; 以及ii）探索组织微环境的作用以及这些多种因素如何促成肿瘤起始 和进步。在处理最致命的乳房类型时，这些努力特别值得 癌、化生性乳腺癌（MBC）。识别组织成分和信号通路， 有助于这些癌症的出现，以便为患者设计更成功的治疗方法， 被诊断为MBC的患者确实具有最重要的临床意义。这份申请是我个人 Tlsty实验室对乳腺基质-上皮相互作用的长期兴趣的“扭曲” 肿瘤发生它的核心概念依赖于越来越受欢迎的概念，即癌症的进展需要 一个有益的肿瘤微环境（TME）。TME的产生源于：获得癌症- 相关的成纤维细胞特征，巨噬细胞类型的转变，ECM特征的改变， 促进或抵消肿瘤生长，破坏免疫反应，扩张和渗漏的脉管系统， 缺氧环境与上皮细胞可塑性增加相关。这样的表型被例示为 在以促结缔组织增生基质伴广泛和改变的ECM沉积为特征的侵袭性肿瘤中 以MBC为代表。因此，在MBC中看到的ECM组成的不平衡是广泛的结构性变化的结果。 以及由基质和上皮细胞性质的改变引起的功能性基质变化。我们 一个挑衅性的预测，一个特定的ECM/基质组成可能会识别癌症与最差的结果 在乳腺癌亚型（管腔型、Her 2阳性、基底样）中， MBC和基底细胞样癌，但也适用于晚期复发的管腔型乳腺癌。获得宝贵 i）通过比较，鉴定MBC进展的基质驱动因子（和抑制因子）， 乳腺肿瘤（包括MBC）和无病乳腺标本的ECM蛋白质组学分析， 强调翻译后修饰状态; ii）查询基因表达数据库以进行上调 (or下调）这些ECM蛋白在乳腺癌亚型（管腔型，Her 2阳性，基底型， claudin低）通过数据挖掘; iii）测试这些ECM蛋白中的一些驱动（或抑制）细胞的能力 使用3D细胞培养模型的体外可塑性（多系定型和上皮间质转化）; 和iv）在鼠中体内证实这些ECM蛋白的促（或抗）化生/致瘤活性 异种移植模型。我在蛋白质生物化学，细胞生物学和小鼠特征方面的丰富经验 模型结合我最近对数据挖掘和多重免疫组织化学的兴趣，使我处于一个 最佳位置的新追求ECM的变化的基础进展的MBC。