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.

项目摘要 许多侵袭性癌症具有由异质性间质和间质细胞组成的强大的肿瘤微环境。 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靶点， 研究包括肿瘤细胞外源性靶点，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因素 进展从利用靶向CAF的治疗潜力的初步尝试， 很明显，靶向CAF作为大量细胞群体是不够的。因此，已经做出了努力， 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 通常由两个总体组描述：肌成纤维细胞CAF（myCAF）和炎性CAF（iCAF）。 在胰腺癌中，观察到myCAF与肿瘤相邻，而iCAF距离肿瘤细胞更远。 虽然确定CAF的亚型是必要的第一步，但新的治疗方法的开发将 可能需要鉴定CAF亚型的特定功能。为此，Wnt 2已被鉴定为 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是未知的。甲状腺未分化癌（ATC）是一种致死性疾病（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。的组成 ATC中的肿瘤间质在很大程度上尚未被探索。我的初步工作确定了一个突出的成纤维细胞 表达WNT 2的ATC中的群体。由于已知ATC相对于其他细胞具有上调的Wnt信号传导， 甲状腺肿瘤，这提供了一个独特的机会来研究CAF驱动的Wnt信号转导的动力学。的 本提案的目的是确定甲状腺癌中存在的CAF亚型，并确定其功能。 CAF衍生的Wnt 2对肿瘤生长的作用。我假设不同的CAF群体促进肿瘤生长 与甲状腺癌的侵袭性有着独特的空间关系。测试我 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是一个 主要是惰性甲状腺癌，可以转化为ATC在体内，使其成为理想的检查， CAF促进疾病进展的能力。在目标1中，我将阐明ATC中存在的CAF亚型， PTC和探针Wnt配体-受体相互作用。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>40例原发性甲状腺癌患者CAF 我们实验室收集的培养物，以证明CAF衍生的Wnt 2信号传导在PTC中的作用 和ATC肿瘤细胞和自分泌形成CAFs的表型。在完成这些研究后，我将 首次明确了甲状腺癌中CAFs的异质性，并描述了一种潜在的新治疗方法 适用于多种癌症类型CAF的靶点。