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.

项目总结： 在美国，甲状腺癌正在迅速增加，乳头状甲状腺癌(PTC)是最常见的亚型 打字。虽然大多数患者的甲状腺癌在最初的治疗后被治愈，但很大一部分患者 患者会患上侵袭性疾病。一些PTC甚至发展成间变性甲状腺癌(ATC)， 极具致命性和抗药性的疾病，4个月存活率极低。肿瘤相关成纤维细胞 (CAF)已被证明在一些癌症的侵袭行为和进展中发挥重要作用， 包括胰腺癌和三阴性乳腺癌。来自我们小组的初步数据显示，ATC 由大量表达成纤维细胞激活蛋白α(FAP)的促肿瘤CAF定义 和WNT-2配体。这些CAF位于肿瘤-间质界面上，可能支持去分化和 邻近肿瘤细胞的干细胞样表型，由TNC的表达定义。我们发现那很小 这些FAP+CAF中的许多存在于PTC的子集中，并作为未来疾病的强大生物标志物 进步。我们的初步研究提供了令人信服的证据，证明CAF亚集和CAF衍生的WNT 配体推动肿瘤的生长和进展，Wnt信号水平的升高与不良相关 分化和侵袭性疾病。该提案的总体目标是确定CAF在甲状腺中的作用。 恶性肿瘤及其旁分泌Wnt信号如何支持侵袭性肿瘤行为。 为了评估CAF在甲状腺癌中的作用，我们收集了大约300名甲状腺疾病患者的队列 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 含50例甲状腺癌原发癌患者的甲状腺生物库及相应的CAF培养。这 Biobank允许我们的团队研究甲状腺癌的微环境 形态和基因改变。最后，我们建立了一个患者来源的异种甲状腺移植小鼠模型。 研究甲状腺癌的体内生物学并测试新的治疗方法(包括抗WNT药物) 甲状腺癌对标准护理治疗具有抵抗力。在这个提案中，我们将检验假设 不同的CAF亚群(FAP+Wnt-2+)存在于甲状腺癌中，它们的分泌体驱动Wnt- 介导旁分泌信号促进肿瘤进展。在目标1中，我们将定义Wnt信号在 甲状腺癌、甲状腺癌和复合性肿瘤中甲状腺CAF的异质性显示两者之间的过渡 形态特征。在目标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。在目标3中，我们将调查WNT阻塞间质重组和 ATC的治疗。了解CAF和WNT信号的作用将极大地改进检测 以及治疗最具侵袭性的甲状腺癌。ATC的治疗选择有限，而且令人沮丧 平均生存期为4个月。这些目标的成功完成将直接导致新型药物的临床试验 直接针对促进肿瘤的间质微环境的ATC的治疗。