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

最近的研究表明，Hedgehog (Hh) 信号传导与肿瘤扩张和生存率降低相关 在三阴性乳腺癌 (TNBC) 患者中，这表明 Hh 抑制剂具有潜在的治疗价值。 多项研究强调间充质细胞是 Hh 信号致瘤性的潜在靶标， 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捕获间充质细胞亚型的独特贡献的模型 对 Hh 抑制剂的生长反应。抑制 Hh 信号传导可导致肿瘤扩张或抑制；一个双 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。我们的研究和初步数据支持间充质细胞亚型对 Hh 信号传导的致瘤潜力。我们对成纤维细胞和间充质细胞的个体贡献的评估 干细胞表明间充质生态位组成的变化会影响肿瘤发生信号 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 体外模型能够识别临床挑战性内分泌肿瘤的新靶点。我们的整体 目标是验证体外模型以预测治疗效果并识别相关的致癌线索 基质的组成可用作致癌标记物和靶点以改善治疗 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 相邻基质的组成。我们的假设是根据之前的研究和我们的研究提出的 初步数据支持间充质细胞亚型在肿瘤细胞反应中的独特贡献 至 Hh 信令。我们的基本原理是评估间充质细胞和免疫细胞之间的相互作用 肿瘤对 Hh 抑制剂敏感性的生态位对于理解肿瘤向 Hh 抑制剂的转变非常有价值。 由基质驱动的治疗抵抗。提出以下目标： 目标 1- 模型旁分泌 Hh 信号传导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 通过评估对 Hh 抑制的反应，目标 3-免疫细胞对 Hh 致癌性的影响 旁分泌信号。这些目标将支持在我们的体外模型中重现体内观察结果 证实间充质细胞生态位对 Hh 信号致瘤性的影响。这个贡献是 意义重大，因为它将为肿瘤细胞行为的调节提供新的生物学见解 基质生态位的变化并确定基质细胞成分在 Hh 中的治疗价值 发信号。该技术具有创新性，因为它提供了一种简单且可定制的文化模型 用于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。

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.