The Role of Cancer-Associated Fibroblasts in Thyroid Carcinoma

癌症相关成纤维细胞在甲状腺癌中的作用

• 批准号: 10682554
• 负责人: Vivian Lee Weiss
• 金额: $ 38.83万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682554
• 关键词: Academic Medical Centers; Adhesions; Aggressive behavior; Autocrine Communication; Behavior; Benign; Binding; Biological Markers; Biology; Cells; Cellularity; Clinical Trials; Colon Carcinoma; Data; Detection; Development; Diagnostic; Disease; Disease Progression; Disease Resistance; Fibroblasts; Future; Goals; Grant; Heterogeneity; Immunofluorescence Immunologic; Indolent; Institution; Invaded; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of thyroid; Mediating; Modeling; Molecular; Morphology; Mutation; Neoplastic Processes; Nomenclature; Organoids; Pancreas; Papillary thyroid carcinoma; Paracrine Communication; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Proliferating; Proteins; Research; Role; Signal Transduction; Stromal Neoplasm; Study models; Supporting Cell; Tenascin; Testing; Therapeutic; Thyroid Diseases; Thyroid Gland; Thyroid carcinoma; Tissues; Treatment-Related Cancer; Tumor Promotion; Universities; WNT Signaling Pathway; Washington; Xenograft procedure; anaplastic thyroid cancer; biobank; biomarker identification; cancer type; cell dedifferentiation; cohort; effective therapy; efficacy evaluation; fibroblast activation protein alpha; fibroblast-activating factor; improved; in vivo; inhibitor; malignant breast neoplasm; mouse model; neoplastic; neoplastic cell; new therapeutic target; novel; novel therapeutics; paracrine; patient derived xenograft model; prevent; proto-oncogene protein Wnt-2; receptor; recruit; refractory cancer; single cell sequencing; single-cell RNA sequencing; standard of care; stem; targeted cancer therapy; targeted treatment; therapeutic target; therapeutically effective; thyroid neoplasm; transcriptomics; triple-negative invasive breast carcinoma; tumor; tumor behavior; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY: Thyroid cancer is rapidly increasing in the U.S., with papillary thyroid carcinoma (PTC) as the most common sub- type. While most patients are cured of their thyroid cancer following initial treatment, a significant portion of patients develop aggressive disease. Some PTCs even develop into anaplastic thyroid carcinoma (ATC), a highly lethal and treatment-resistant disease with an abysmal 4-month survival. Cancer-associated fibroblasts (CAFs) have been shown to play an important role in the aggressive behavior and progression of some cancers, including pancreas and triple-negative breast cancer. Preliminary data from our group show that ATCs are defined by a large population of tumor-promoting CAFs that express Fibroblast Activation Protein Alpha (FAP) and Wnt-2 ligand. These CAFs sit along the tumor-stromal interface and likely support a de-differentiated and stem-like phenotype in adjacent tumor cells, as defined by tenascin-C (TNC) expression. We find that small numbers of these FAP+ CAFs are present in a subset of PTCs and serve as a robust biomarker of future disease progression. Our preliminary studies provide compelling evidence that CAF subsets and CAF-derived Wnt ligands drive tumor growth and progression, with elevated levels of Wnt signaling associated with poorly differentiated and aggressive disease. The overall goal of this proposal is to determine the role of CAFs in thyroid malignancy and how their paracrine Wnt signaling supports aggressive tumor behavior. To evaluate the role of CAFs in thyroid cancer, we have collected a cohort of ~300 patients with thyroid disease from Vanderbilt University Medical Center and the University of Washington. We have also created the only thyroid biobank with >50 primary-patient derived thyroid cancer organoids and corresponding CAF cultures. This biobank allows our team to study the thyroid cancer microenvironment across a heterogeneous landscape of morphologies and genetic alterations. Finally, we create a patient-derived xenograft mouse model for thyroid cancer to study the in vivo biology of thyroid cancer and to test new therapeutics (including anti-Wnt drugs) for thyroid cancers resistant to standard-of-care therapy. In this proposal, we will test the hypothesis that distinct CAF subsets (FAP+ Wnt-2+) are present in thyroid cancers and that their secretome drives Wnt- mediated paracrine signaling for tumor progression. In Aim 1, we will define the role of Wnt signaling in thyroid CAF heterogeneity in ATCs, PTCs, and composite tumors showing the transition between both morphologies. In Aim 2, we will define the molecular interaction between Wnt-2 ligand and Tenascin-C (TNC) to promote a stem-like phenotype in ATC. In Aim 3, we will investigate Wnt blockade for stromal reorganization and treatment of ATC. An understanding of the role of CAFs and Wnt signaling will dramatically improve the detection and treatment of the most aggressive forms of thyroid cancer. ATC has limited treatment options and a dismal average survival of ~4 months. Successful completion of these goals will lead directly to clinical trials of novel therapies for ATC that directly target the tumor-promoting stromal microenvironment.

项目摘要： 甲状腺癌在美国迅速增加，乳头状甲状腺癌（PTC）是最常见的亚下 类型。虽然大多数患者在初次治疗后都可以治愈其甲状腺癌，但很大一部分 患者患上侵略性疾病。一些PTC甚至会发展为甲状腺甲状腺癌（ATC），A 高度致命和耐药性疾病具有糟糕的4个月生存期。癌症相关的成纤维细胞 （CAF）已被证明在某些癌症的攻击行为和进展中起着重要作用， 包括胰腺和三阴性乳腺癌。我们小组的初步数据表明ATC是 由表达成纤维细胞激活蛋白α（FAP）的大量促进肿瘤的CAF定义 和Wnt-2配体。这些CAF坐落在肿瘤界面界面，可能支持脱不同的界面和 由Tenascin-C（TNC）表达定义，相邻肿瘤细胞中的茎样表型。我们发现很小 这些FAP+ CAF的数量存在于PTC的一部分中，并作为未来疾病的强大生物标志物 进展。我们的初步研究提供了令人信服的证据，表明CAF子集和CAF衍生的Wnt 配体驱动肿瘤的生长和进展，Wnt信号的水平升高与较差 分化和侵略性疾病。该提案的总体目标是确定CAF在甲状腺中的作用 恶性肿瘤以及其旁分泌Wnt信号如何支持攻击性肿瘤行为。 为了评估CAF在甲状腺癌中的作用，我们收集了约300例甲状腺疾病的队列 来自范德比尔特大学医学中心和华盛顿大学。我们还创建了唯一的 甲状腺生物库，具有> 50个原发性衍生的甲状腺癌器官和相应的CAF培养物。这 Biobank允许我们的团队研究甲状腺癌微环境，从 形态和遗传改变。最后，我们为甲状腺创建了一种患者衍生的异种移植小鼠模型 癌症研究甲状腺癌的体内生物学，并测试新的治疗剂（包括抗Wnt药物）的癌症 甲状腺癌对护理标准疗法有抵抗力。在此提案中，我们将检验以下假设 甲状腺癌中存在不同的CAF子集（FAP+ Wnt-2+） 用于肿瘤进展的介导的旁分泌信号传导。在AIM 1中，我们将定义Wnt信号在 ATC，PTC和复合肿瘤中的甲状腺CAF异质性，显示两者之间的过渡 形态。在AIM 2中，我们将定义Wnt-2配体与Tenascin-C（TNC）之间的分子相互作用 在ATC中促进茎状表型。在AIM 3中，我们将调查Wnt封锁的基质重组和 ATC的处理。了解CAF和WNT信号的作用将大大改善检测 以及最具侵略性的甲状腺癌。 ATC的治疗选择有限，很沮丧 平均生存率约为4个月。这些目标的成功完成将直接导致新颖的临床试验 直接针对促肿瘤基质微环境的ATC的ATC疗法。