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，Hedgehog（Hh）信号与肿瘤扩张和生存率降低相关 在三阴性乳腺癌（TNBC）患者中，提示Hh抑制剂的潜在治疗价值。 一些研究已经强调间充质细胞是Hh信号传导致瘤性的潜在靶点， 但它们的诊断价值和对Hh抑制剂治疗反应的影响尚未确定。 一个主要的限制是缺乏模型，捕捉不同的贡献，间充质细胞亚型中， 对Hh抑制剂的生长反应。抑制Hh信号传导可导致肿瘤扩大或抑制; 可能对Hh治疗的肿瘤的治疗结果产生负面影响的模式生长机制 抑制剂的我们的研究和初步数据支持间充质细胞亚型在肿瘤发生中的影响。 Hh信号传导的致瘤潜力。我们评估了成纤维细胞和间充质细胞的个体贡献， 干细胞提示间充质生态位组成的变化影响了肿瘤的发生信号， Hh通路和对Hh抑制剂的反应。我们的长期目标是提供仿生和多细胞类型的 体外模型，使新的目标，在临床挑战内分泌肿瘤的鉴定。我们的整体 目的是验证预测治疗效果的体外模型，并确定与肿瘤相关的致癌线索。 涉及可用作致癌标志物和靶点以改善治疗性肿瘤的基质的组成， 对Hh抑制剂的反应。我们的中心假设是Hh信号传导的致癌性受到Hh信号的调节。 相邻基质的组成。我们的假设是基于以前的研究和我们的 支持间充质细胞亚型在肿瘤细胞应答中的独特作用的初步数据 到Hh信令。我们的基本原理是评估间充质和免疫细胞之间的相互作用， 肿瘤对Hh抑制剂敏感性的小生境对于理解肿瘤向Hh抑制剂的转化将是有价值的。 由基质驱动的治疗抗性。提出了以下目标：目标1-模型旁分泌Hh 信号传导对干性和治疗抗性的贡献，目的2-Hh旁分泌模型的体内验证 通过评价对Hh抑制的反应，目的3-免疫细胞在Hh致瘤性中的影响 旁分泌信号这些目标将支持在我们的体外模型中的体内观察的重演， 证实间充质细胞龛在Hh信号传导的致瘤性中的影响。这种贡献 重要的是，它将提供新的生物学见解，以调节肿瘤细胞的行为， 转移间质生态位和建立间质细胞成分在Hh的治疗价值 发信号。该技术是创新的，因为它提供了一个简单的和可定制的文化模型， 这是为了评估肿瘤向更具侵袭性状态的转变以及Hh中免疫细胞的影响， 旁分泌信号