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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要许多侵袭性癌症具有由异质基质和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在靶标，但靶向肿瘤基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。从初步尝试利用靶向 CAF 的治疗潜力，它已成为显然，将 CAF 作为大量细胞群是不够的。因此，人们一直在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来描述：肌成纤维细胞 CAF (myCAF) 和炎症 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。虽然定义 CAF 亚型是必要的第一步，但新型治疗方法的开发将可能需要识别 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 信号传导在肿瘤的进展仍然很大程度上未知。甲状腺未分化癌 (ATC) 是一种致命性疾病（约 3-5 个月）中位生存期），肿瘤基质丰富且没有有效的治疗选择。的组成 ATC 中的肿瘤基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 ATC 中表达 WNT2 的群体。众所周知，ATC 相对于其他信号传导上调 Wnt 信号传导甲状腺肿瘤，这为研究 CAF 驱动的 Wnt 信号传导动力学提供了独特的机会。这该提案的目标是定义甲状腺癌中存在的 CAF 亚型并确定其功能 CAF 衍生的 Wnt2 对肿瘤生长的作用。我假设不同的 CAF 群体促进肿瘤生长甲状腺癌中通过 Wnt 信号传导进行的侵袭和侵袭具有独特的空间关系。为了测试我的假设，我将在 ATC 模型和甲状腺乳头状癌 (PTC) 模型中进行实验。 PTC 是一个主要是惰性甲状腺癌，可在体内转化为 ATC，使其成为检查甲状腺癌的理想选择 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 亚型和 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，我将利用 >40 个原发患者甲状腺癌 CAF 我们实验室收集的培养物用于证明 CAF 衍生的 Wnt2 信号传导在 PTC 上的旁分泌作用和ATC肿瘤细胞和自分泌来塑造CAF的表型。在完成这些研究时，我将首次定义了甲状腺癌中 CAF 的异质性并描述了一种潜在的新型治疗方法适用于多种癌症类型的 CAF 的目标。