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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

基本信息

批准号：
10724829
负责人：
Maribella Domenech
金额：
$ 15.21万
依托单位：
UNIVERSITY OF PUERTO RICO MAYAGUEZ
依托单位国家：
美国
项目类别：
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

项目摘要

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)信号与肿瘤的扩大和生存率的降低有关在三阴性乳腺癌(TNBC)患者中，提示HH抑制剂具有潜在的治疗价值。一些研究强调间充质细胞是HH信号致瘤性的潜在靶点，然而，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来捕捉间充质细胞亚型在对HH抑制剂的生长反应。抑制HH信号可导致肿瘤扩张或抑制；可能对HH治疗肿瘤的治疗结果产生负面影响的模式生长机制抑制剂。我们的研究和初步数据支持间充质细胞亚型对 HH信号的致瘤潜能。我们对成纤维细胞和间质的个体贡献的评估干细胞提示间充质壁龛成分的变化会影响肿瘤发生的信号 HH途径和对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能够在临床挑战的内分泌肿瘤中识别新靶点的体外模型。我们的整体目的是验证用于预测疗效和识别相关致癌线索的体外模型。可用作肿瘤标志物和靶点以提高治疗效果的间质成分对HH抑制剂的反应。我们的中心假设是HH信号的致瘤性受相邻基质的组成。我们的假设是基于之前的研究和我们的支持间充质细胞亚型在肿瘤细胞反应中的不同贡献的初步数据转到HH信号。我们的理论基础是对间充质和免疫细胞之间相互作用的评估肿瘤对HH抑制剂敏感性的利基位置将有助于理解肿瘤向由基质驱动的治疗抵抗。提出了以下目标：目标1-模型旁分泌HH 信号对干性和治疗耐药性的贡献，目标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和证实间充质细胞生态位在HH信号致瘤性中的影响。这一贡献是因为它将为肿瘤细胞行为的调节提供新的生物学见解 HH间质生态位的改变及间质细胞成分的治疗价值发信号。该技术具有创新性，因为它提供了简单且可定制的文化模型以评估肿瘤向更具侵袭性状态的转变以及免疫细胞在HH中的影响旁分泌信号。