Cancer-associated fibroblasts promote thyroid cancer malignancy through Wnt signaling

癌症相关成纤维细胞通过 Wnt 信号传导促进甲状腺癌恶性

• 批准号: 10677942
• 负责人: Matthew A Loberg
• 金额: $ 3.29万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677942
• 关键词: Actins; Aggressive behavior; Automobile Driving; Cell surface; Cells; Coculture Techniques; Colorectal Cancer; Common Carcinoma; Communication; Development; Disease; Disease Progression; Distal; Distant; Experimental Designs; Fibroblasts; Future; Genes; Goals; Growth; Head and neck structure; Immune; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunotherapy; Indolent; Inflammatory; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of thyroid; Modeling; Molecular Target; Monitor; Morphology; Mus; Myofibroblast; Organoids; Papillary thyroid carcinoma; Patients; Phenotype; Population; Proliferating; Publishing; Resolution; Role; Shapes; Signal Transduction; Signaling Protein; Smooth Muscle; Space Perception; Specimen; Stromal Cells; System; Techniques; Testing; Therapeutic; Thyroid Gland; Thyroid carcinoma; Time; Training; Translational Research; Transplantation; Tumor Cell Invasion; Tumor Promotion; WNT Signaling Pathway; WNT2 gene; Work; Xenograft procedure; anaplastic thyroid cancer; anticancer research; autocrine; biobank; cancer cell; cancer heterogeneity; cancer subtypes; cancer type; career; cohort; differential expression; digital; effective therapy; efficacious treatment; exome sequencing; experimental study; fibroblast activation protein alpha; genetic signature; improved; in vivo; inhibitor; insight; malignant breast neoplasm; mouse model; nano-string; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; overexpression; pancreatic cancer model; paracrine; pharmacologic; receptor; response; single-cell RNA sequencing; spatial relationship; stem; therapeutic target; thyroid neoplasm; transcriptome sequencing; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY Many aggressive cancers have a robust tumor microenvironment composed of heterogenous stromal and immune cells. Although the advent of immune checkpoint inhibitors has shifted therapeutic targets of cancer research to include tumor-cell extrinsic targets, the therapeutic potential of targeting the tumor stroma remains underexploited. Recently, cancer-associated fibroblasts (CAFs) have been implicated as drivers of disease progression. From preliminary attempts to harness the therapeutic potential of targeting CAFs, it has become clear that targeting CAFs as a bulk population of cells will not be sufficient. As such, there have been efforts in breast and pancreatic cancer to define the heterogeneity of CAFs. These efforts have yielded diverse subtypes commonly described by two overarching groups: myofibroblast CAFs (myCAFs) and inflammatory CAFs (iCAFs). In pancreatic cancer, myCAFs are observed to be tumor-adjacent and iCAFs are more distant from tumor cells. While defining subtypes of CAFs is a necessary first step, the development of novel therapeutic approaches will likely require the identification of specific functions of CAF subtypes. To this end, Wnt2 has been identified as upregulated in CAFs from pancreatic, breast, and colorectal cancer, yet the role of CAF-driven Wnt signaling on tumor progression remains largely unknown. Anaplastic thyroid carcinoma (ATC) is a lethal disease (~3-5 month median survival) with an abundant tumor stroma and no efficacious treatment options. The composition of the tumor stroma in ATC has been largely unexplored. My preliminary work identifies a prominent fibroblast population in ATC that expresses WNT2. As ATC is known to have upregulated Wnt signaling relative to other thyroid neoplasms, this provides a unique opportunity to study the dynamics of CAF-driven Wnt signaling. The goal of this proposal is to define the CAF subtypes present in thyroid carcinoma and determine the functional role of CAF-derived Wnt2 on tumor growth. I hypothesize that distinct CAF populations promote tumor growth and invasion in thyroid carcinoma through Wnt signaling and have unique spatial relationships. To test my hypothesis, I will perform experiments in ATC models and papillary thyroid carcinoma (PTC) models. PTC is a predominantly indolent thyroid carcinoma that can transform to ATC in vivo, making it ideal for examining the ability of CAFs to promote disease progression. In aim 1, I will elucidate subtypes of CAFs present in ATC and PTC and probe Wnt ligand-receptor interactions. Further, I will determine spatial resolution of myCAF and iCAF fibroblast populations in thyroid carcinoma. In aim 2, I will utilize >40 primary patient thyroid carcinoma CAF cultures that our lab has collected to demonstrate the role of CAF-derived Wnt2 signaling both paracrine on PTC and ATC tumor cells and autocrine to shape the phenotype of CAFs. In completing these studies, I will for the first time define the heterogeneity of CAFs in thyroid carcinoma and characterize a potential novel therapeutic target applicable to CAFs in multiple cancer types.

项目总结 许多侵袭性癌症具有强大的肿瘤微环境，由异质间质和 免疫细胞。尽管免疫检查点抑制剂的出现改变了癌症的治疗目标 包括肿瘤细胞外在靶点的研究，靶向肿瘤间质的治疗潜力仍然存在 开发不足。最近，癌症相关成纤维细胞(CAF)被认为是疾病的驱动力。 进步。从初步尝试利用靶向CAF的治疗潜力，它已经成为 显然，将CAF作为大量细胞群体是不够的。因此，已经在以下方面做出了努力 乳腺癌和胰腺癌来定义CAF的异质性。这些努力产生了不同的亚型 通常由两个主要组描述：肌成纤维细胞CAF(MyCAF)和炎症性CAF(ICAF)。 在胰腺癌中，myCAF被观察到与肿瘤相邻，而iCAF离肿瘤细胞更远。 虽然确定CAF的亚型是必要的第一步，但开发新的治疗方法将 可能需要确定CAF亚型的特定功能。为此，WNT2被确定为 在胰腺癌、乳腺癌和结直肠癌的CAF中上调，但CAF驱动的Wnt信号转导在 肿瘤的进展在很大程度上仍不清楚。间变性甲状腺癌(ATC)是一种致命的疾病(约3-5个月 中位生存期)，肿瘤间质丰富，没有有效的治疗选择。这份报告的组成 ATC中的肿瘤间质在很大程度上还没有被探索。我的初步工作确定了一种突出的成纤维细胞 ATC中表达WNT2的种群。因为已知ATC已经上调了WNT信号相对于其他 对于甲状腺肿瘤，这为研究CAF驱动的Wnt信号的动力学提供了一个独特的机会。这个 这项建议的目标是定义甲状腺癌中存在的CAF亚型，并确定功能性 CAF来源的WNT2在肿瘤生长中的作用。我假设不同的CAF人群促进了肿瘤的生长 并通过Wnt信号在甲状腺癌中侵袭，并具有独特的空间关系。测试我的 假设，我将在ATC模型和乳头状甲状腺癌(PTC)模型中进行实验。PTC是一种 以惰性甲状腺癌为主，可在体内转化为ATC，使其成为检查 CAF促进疾病进展的能力。在目标1中，我将阐明ATC和ATC中存在的CAF的亚型 PTC和探针Wnt配体-受体的相互作用。此外，我将确定myCAF和ICAF的空间分辨率 甲状腺癌中的成纤维细胞群。在目标2中，我将使用&gt；40名原发性甲状腺癌患者CAF 我们实验室收集的培养物证明了CAF来源的WNT2信号在PTC上的旁分泌信号的作用 ATC肿瘤细胞和自分泌来塑造CAF的表型。在完成这些研究后，我将为 首次明确甲状腺癌组织中CAF的异质性并表征潜在的新治疗方法 靶点适用于多种癌症类型的CAF。