Distinct contributions of mesenchymal cell niches in the therapeutic potential of the hedgehog pathway in triple negative breast cancer

间充质细胞生态位对三阴性乳腺癌刺猬通路治疗潜力的独特贡献

• 批准号: 10666446
• 负责人: Maribella Domenech
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF PUERTO RICO MAYAGUEZ
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10666446
• 关键词: Adipose tissue; Biological; Biomimetics; Breast Cancer Patient; CD44 gene; Cell model; Cells; Cellular Structures; Clinical; Coculture Techniques; Cues; Data; Drug Modelings; Drug Screening; Endocrine Gland Neoplasms; Erinaceidae; Evaluation; Fibroblasts; Genomics; Goals; Growth; Immune; Individual; Invaded; Ligands; MDA-MB-468; Macrophage; Mammary Neoplasms; Mesenchymal; Mesenchymal Cell Neoplasm; Mesenchymal Stem Cells; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Modality; Modeling; Monitor; Oncogenic; Paracrine Communication; Pathway interactions; Patient Selection; Phenotype; Physiological; Role; SHH gene; Sampling; Signal Transduction; Stromal Cells; Surface; Survival Rate; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor Cell Invasion; Tumor Expansion; Tumor Suppression; Tumor Volume; Tumor-infiltrating immune cells; Tumorigenicity; United States National Institutes of Health; Validation; Xenograft Model; behavioral response; cancer stem cell; cancer subtypes; cell behavior; cell type; diagnostic value; drug sensitivity; improved; in vitro Model; in vivo; inhibitor; innovation; insight; mimetics; neoplastic cell; novel; paracrine; pharmacologic; predictive modeling; receptor; response; smoothened signaling pathway; stemness; therapy outcome; therapy resistant; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor xenograft; tumorigenic

Recent studies show that Hedgehog (Hh) signaling correlates with tumor expansion and reduced survival rates in triple negative breast cancer (TNBC) patients, suggesting a potential therapeutic value for Hh inhibitors. Several studies have highlighted mesenchymal cells as potential targets in the tumorigenicity of Hh signaling, yet their diagnostic value and influence in the therapeutic response of Hh inhibitors have not been established. A main limitation is the lack of models that capture distinct contributions of mesenchymal cell sub-types in the growth response to Hh inhibitors. Inhibition of Hh signaling can lead to tumor expansion or suppression; a bi- modal growth mechanism that can negatively impact the therapeutic outcome in tumors treated with Hh inhibitors. Our studies and preliminary data support the influence of mesenchymal cell sub-types in the tumorigenic potential of Hh signaling. Our evaluation of individual contributions of fibroblasts and mesenchymal stem cells suggest that changes in the composition of the mesenchymal niche influence tumorigenic signals of the Hh pathway and response to Hh inhibitors. Our long-term goal is to provide biomimetic and multi-cell type in vitro models that enable the identification of new targets in clinically challenged endocrine tumors. Our overall goal is to validate an in vitro model for prediction of therapeutic efficacy and identify oncogenic cues associated to the composition of the stroma that can be used as oncogenic markers and targets to improve therapeutic response to Hh inhibitors. Our central hypothesis is that the oncogenicity of Hh signaling is regulated by the composition of the adjacent stroma. Our hypothesis has been formulated based on previous studies and our preliminary data supporting distinct contributions of mesenchymal cell sub-types in the response of tumor cells to Hh signaling. Our rationale is that the evaluation of the interplay between the mesenchymal and immune cell niches in the sensitivity of tumors to Hh inhibitors will be valuable towards understanding tumor transitions to therapeutic resistance driven by the stroma. The following aims are proposed: Aim 1- Model paracrine Hh signaling contribution to stemness and resistance to therapy, Aim 2- In vivo validation of a Hh paracrine model through evaluation of response to Hh inhibition, and Aim 3- Impact of immune cells in the oncogenicity of Hh paracrine signaling. These aims will support recapitulation of in vivo observations in our in vitro models and confirm the influence of the mesenchymal cell niche in the tumorigenicity of Hh signaling. This contribution is significant as it will provide new biological insights into the modulation of tumor cell behavior in response to shifts in the stromal niche and establish the therapeutic value of stromal cell components in Hh signaling. The technology is innovative because it provides with a simple and customizable culture model in which to evaluate tumor transitions towards a more aggressive state and the impact of immune cells in Hh paracrine signaling.

最近的研究表明，刺猬（HH）信号传导与肿瘤膨胀和存活率降低相关 在三重阴性乳腺癌（TNBC）患者中，表明HH抑制剂具有潜在的治疗价值。 几项研究突出了间充质细胞，作为HH信号传导肿瘤性的潜在靶标， 然而，尚未建立它们在HH抑制剂治疗反应中的诊断价值和影响。 一个主要限制是缺乏捕获间充质细胞子类型的不同贡献的模型 对HH抑制剂的增长反应。 HH信号的抑制会导致肿瘤扩张或抑制；双 模态生长机制可能会对HH治疗的肿瘤的治疗结果产生负面影响 抑制剂。我们的研究和初步数据支持间充质细胞亚型在 HH信号传导的致瘤潜力。我们对成纤维细胞和间质的个人贡献的评估 干细胞表明，间充质小众组成的变化影响 HH途径和对HH抑制剂的反应。我们的长期目标是在 可以在临床挑战的内分泌肿瘤中鉴定新靶标的体外模型。我们的整体 目标是验证一个体外模型，以预测治疗功效并确定相关的致癌性线索 对于基质的组成，可以用作致癌标记和靶标以改善治疗性 对HH抑制剂的反应。我们的中心假设是HH信号的致癌性受到调节 相邻基质的组成。我们的假设是根据先前的研究和我们的 初步数据支持间充质细胞亚型在肿瘤细胞反应中的不同贡献 发信号。我们的理由是评估间充质和免疫细胞之间的相互作用 肿瘤对HH抑制剂的敏感性中的壁ni，对于理解肿瘤转变至 由基质驱动的治疗抗性。提出了以下目的：目标1-模型旁分泌HH 信号传导对干性和对治疗的抵抗力的贡献，AIM 2-在体内验证HH旁分泌模型 通过评估对HH抑制的反应，并瞄准3-免疫细胞对HH致癌性的影响 旁分泌信号传导。这些目标将支持我们体外模型中体内观察的概括， 确认间充质细胞生态位在HH信号传导的致瘤性中的影响。这个贡献是 意义重大，因为它将为响应于肿瘤细胞行为的调节提供新的生物学见解 基质小众的变化并建立HH中基质细胞成分的治疗值 信号。该技术具有创新性，因为它为简单且可自定义的文化模型提供 评估肿瘤向更具侵略性状态和免疫细胞在HH中的影响 旁分泌信号传导。