Defining the formation and function of carcinoma-associated mesenchymal stem cells in the ovarian cancer microenvironment

定义卵巢癌微环境中癌相关间充质干细胞的形成和功能

• 批准号: 10444414
• 负责人: Lan Coffman
• 金额: $ 8.86万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10444414
• 关键词: Acidosis; Activities of Daily Living; Adipocytes; Bone Marrow; Bone Morphogenetic Proteins; Carcinoma; Cell Hypoxia; Cells; Chemicals; Chemoresistance; Complex; DNA Methylation; Data; Development; Diffuse; Elements; Epigenetic Process; Exhibits; Fibroblasts; Foundations; Future; Genotype; Goals; Growth; HIF1A gene; Hyperactivity; Hypoxia; Hypoxia-Inducible Factor Pathway; In Vitro; Intra-abdominal; Knock-out; Knowledge; Malignant - descriptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediator of activation protein; Mentorship; Mesenchymal Stem Cells; Modification; Molecular; Multipotent Stem Cells; Mutation; Myofibroblast; Neoplasm Metastasis; Non-Malignant; Normal Cell; Normal tissue morphology; Phenotype; Physicians; Play; Population; Property; Research; Research Training; Role; Scientist; Signal Pathway; Site; Stromal Cells; Stromal Neoplasm; System; Training; Treatment outcome; Tumor Promotion; Woman; Work; behavior influence; cancer stem cell; career; cell growth; cell type; conditioning; epigenetic regulation; improved outcome; in vivo; innovation; intraperitoneal; migration; molecular phenotype; mortality; multipotent cell; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; protein expression; skills; small molecule; stem cell function; stem-like cell; stemness; success; tumor; tumor growth; tumor microenvironment; tumorigenic

ABSTRACT: Ovarian cancer is the most deadly US gynecologic malignancy with a mortality rate that exceeds 50% at 5 years. Ovarian cancer is characterized by early intraperitoneal metastasis and the development of a complex microenvironment which supports tumor cell growth, survival and spread. Understanding and eventually targeting this cancer-promoting tumor microenvironment offers the potential for powerful new therapeutic approaches. My ultimate goal is to become a world-class independent physician scientist studying the ovarian cancer microenvironment in order to develop new treatments and improve outcomes for women with ovarian cancer. This proposal describes important and innovative research which will lay the foundation for my future career in addition to providing the necessary skills and mentorship vital for my success. The ovarian tumor microenvironment (TME) is a diverse system of cellular and chemical components. The cellular TME includes tumor cells and non-malignant stromal cells. The chemical TME is marked by acidosis and hypoxia. Carcinoma-associated mesenchymal stem cells (CA-MSCs) are multi-potent stromal cells within the cellular TME that can differentiate into multiple pro-tumorigenic stromal cell types including fibroblasts, myofibroblasts, and adipocytes. CA-MSCs are genotypically normal without malignant potential but are functionally different than normal tissue or bone marrow derived MSCs. Compared to normal MSCs, CA-MSCs demonstrate a unique molecular phenotype with very high expression of bone morphogenetic proteins (BMPs). Due to this unique phenotype, these CA-MSCs strongly promote ovarian cancer growth, enhance chemotherapy resistance and enrich the cancer stem cell-like population. How CA-MSCs develop their unique phenotype remains unclear. My preliminary data indicate that tumor secreted factors induce some of the molecular changes associated with CA-MSCs. Another potential mediator of the CA-MSC phenotype is hypoxia. Hypoxia is a hallmark of the chemical TME known to impact normal MSC function. In cancer, hypoxia influences tumor:stromal interactions and hypoxia is a key regulator of BMP expression—high levels of which characterize ovarian cancer CA-MSCs. Preliminary data indicates that hypoxia enhances the ability of tumor cells to induce a CA-MSC expression profile in normal MSCs. While the mechanism of this induction is unknown, given CA-MSCs are genetically normal yet maintain their unique phenotype across multiple passages, tumor-induced epigenetic regulation may be critical to the formation of the CA-MSC phenotype. Indeed, preliminary data indicates CA-MSCs exhibit significant hypomethylation compared to normal MSCs. In addition to influencing the formation of a CA-MSC, hypoxia may also critically regulate the function of CA- MSCs already established in the ovarian TME. My preliminary data suggests that hypoxia maintains the “stemness” of CA-MSCs slowing growth and maintaining differentiation capacity. Further, my data suggests that the hypoxia inducible factor pathway, the main hypoxia signaling pathway, is hyper-active in CA-MSCs compared to normal MSCs. Thus hypoxia may be a critical modulator of CA-MSCs within the ovarian TME. My main research goal is to understand how CA-MSCs obtain their unique phenotype and subsequently interact with and influence the function of the ovarian cancer microenvironment. To achieve this goal, I propose two specific aims: 1) Determine the ability of normal MSCs to acquire a CA-MSC-like phenotype 2) Determine the impact of hypoxia on established CA-MSCs within the tumor microenvironment. In addition to furthering our understanding of CA-MSCs in ovarian cancer, the proposed research and training will cultivate expertise necessary for an independent career studying the ovarian TME. By the end of the training period, I will have developed a novel skill set which merges the expertise of multiple scientific leaders yielding a uniquely trained physician scientist ideal for the study of the ovarian cancer microenvironment.

抽象的： 卵巢癌是美国最致命的妇科恶性肿瘤，5 年死亡率超过 50%。 卵巢癌的特点是早期腹膜内转移和复杂的发展 支持肿瘤细胞生长、存活和扩散的微环境。 针对这种促癌肿瘤微环境提供了强大的新疗法的潜力 我的最终目标是成为一名研究卵巢的世界级独立医师科学家。 癌症微环境，以开发新的治疗方法并改善卵巢癌女性的预后 该提案描述了重要且创新的研究，将为我的未来奠定基础。 除了提供对我的成功至关重要的必要技能和指导之外，我的职业生涯也是如此。 卵巢肿瘤微环境（TME）是一个由细胞和化学成分组成的多样化系统。 细胞性TME包括肿瘤细胞和非恶性基质细胞，化学性TME的特点是酸中毒和酸中毒。 癌相关间充质干细胞（CA-MSC）是体内的多能基质细胞。 细胞 TME 可以分化成多种促肿瘤基质细胞类型，包括成纤维细胞， 肌成纤维细胞和脂肪细胞基因型正常，无恶性潜能，但具有恶性潜能。 与正常 MSC 相比，CA-MSC 的功能与正常组织或骨髓来源的 MSC 不同。 表现出独特的分子表型，骨形态发生蛋白（BMP）的表达非常高。 由于这种独特的表型，这些 CA-MSC 强烈促进卵巢癌的生长，增强化疗效果 抗性并丰富癌症干细胞样群。 CA-MSCs 如何形成其独特的表型仍不清楚。我的初步数据表明肿瘤。 分泌因子诱导一些与 CA-MSC 相关的分子变化。 CA-MSC 表型的一个特点是缺氧 缺氧是已知会影响正常 MSC 的化学 TME 的一个标志。 在癌症中，缺氧影响肿瘤：基质相互作用，缺氧是 BMP 的关键调节因子。 表达——高水平的表达是卵巢癌 CA-MSC 的特征，初步数据表明缺氧。 增强肿瘤细胞在正常 MSC 中诱导 CA-MSC 表达谱的能力。 鉴于 CA-MSC 遗传正常但仍保持其独特性，这种诱导机制尚不清楚 跨多个传代的表型，肿瘤诱导的表观遗传调控可能对形成 事实上，初步数据表明 CA-MSC 相比之下表现出显着的低甲基化。 至正常 MSC。 除了影响 CA-MSC 的形成外，缺氧还可能关键地调节 CA-MSC 的功能。 MSCs 已经在卵巢 TME 中建立。我的初步数据表明缺氧可以维持这种状态。 CA-MSC 的“干性”减缓了生长并保持了分化能力。 相比之下，CA-MSCs 中缺氧诱导因子途径（主要的缺氧信号传导途径）异常活跃 因此，缺氧可能是卵巢 TME 内 CA-MSC 的关键调节剂。 我的主要研究目标是了解 CA-MSCs 如何获得其独特的表型并随后相互作用 为了实现这一目标，我提出两个建议。 具体目标： 1) 确定正常MSC获得CA-MSC样表型的能力 2) 确定缺氧对肿瘤微环境中已建立的 CA-MSC 的影响。 除了进一步加深我们对卵巢癌中 CA-MSC 的了解外，拟议的研究和培训 培训结束后，将培养独立职业研究卵巢 TME 所需的专业知识。 在此期间，我将开发出一套新颖的技能，融合了多个科学领导者的专业知识，从而产生了 经过独特培训的医师科学家，非常适合研究卵巢癌微环境。

项目成果

CDK4/6 inhibition as maintenance and combination therapy for high grade serous ovarian cancer.

• DOI: 10.18632/oncotarget.24585
• 发表时间: 2018-03-20
• 期刊: Oncotarget
• 作者: Iyengar M;O'Hayer P;Cole A;Sebastian T;Yang K;Coffman L;Buckanovich RJ
• 通讯作者: Buckanovich RJ

Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth.

• DOI: 10.1038/s41388-018-0523-6
• 发表时间: 2019-03
• 期刊: Oncogene
• 影响因子: 8
• 作者: McLean K;Tan L;Bolland DE;Coffman LG;Peterson LF;Talpaz M;Neamati N;Buckanovich RJ
• 通讯作者: Buckanovich RJ

Ovarian Carcinoma-Associated Mesenchymal Stem Cells Arise from Tissue-Specific Normal Stroma.

• DOI: 10.1002/stem.2932
• 发表时间: 2019-03
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Coffman LG;Pearson AT;Frisbie LG;Freeman Z;Christie E;Bowtell DD;Buckanovich RJ
• 通讯作者: Buckanovich RJ