Identifying oral cancer stem cell properties affected by the microenvironment

描述（由申请人提供）：来自口腔鳞状细胞癌（oscc）的癌症干细胞（CSCs）有望具有自我更新、转移和治疗耐药性的特性。目前用于研究CSC的模型系统主要是在免疫受损和物种不匹配的基质环境中，不能捕获CSC的所有特性。我们已经开发了“XactMice”，将人类oscc移植到携带人类造血干细胞（HSC）的小鼠体内，这些造血干细胞可以重建人类免疫细胞和其他HSC衍生的人类基质细胞。与免疫受损受体小鼠的oscc相比，xact小鼠的oscc表现出更类似于原代人oscc的病理和分子特征。此外，我们开发了具有自发性oscc的基因工程小鼠模型（GEMMs）。利用这些互补模型，我们将研究微环境对CSC特性的影响，以及这如何改变处理抗性。首先，我们将检查免疫系统和物种匹配的基质细胞是否影响移植的csc的大小和行为，包括癌起始、转移和对辐射的抵抗，辐射是OSCC的主要治疗方法。其次，我们将在共培养系统中将CSC与原发癌相关成纤维细胞（CAFs）或来自同一患者的XactMice的CAFs结合起来，并评估hsc衍生的成纤维细胞是否与原发CAFs对CSC自我更新和侵袭具有相同的影响，以及小鼠成纤维细胞中一小部分hsc衍生的成纤维细胞是否足以促进CSC行为改变。最后，根据我们的初步数据，我们将研究是否抑制TGF？信号传导阻碍CSC癌变、转移和放疗抵抗的特性，并确定哪些TGF？信号元件和靶标参与了CSC的调控。我们对人类肿瘤模型的改造工作为研究OSCC中csc和基质之间的相互作用提供了一个理想的平台。在这种模型中，人类OSCC在免疫能力和物种匹配的基质细胞中生长。这些实验将促进对CSC生物学，肿瘤-基质在人类癌症中的相互作用的理解，以及抑制癌症生长和转移的新靶向分子的优先级。

DESCRIPTION (provided by applicant): Cancer stem cells (CSCs) from oral squamous cell carcinomas (OSCCs) are expected to have properties of self-renewal, metastasis, and treatment resistance. Current model systems for studying CSCs are largely in immune compromised and species-mismatched stromal environments, which do not capture all CSC properties. We have developed "XactMice" in which human OSCCs are transplanted into mice bearing human hematopoietic stem cells (HSC) that reconstitute human immune cells and other HSC-derived human stroma cells. OSCCs in XactMice exhibited pathological and molecular signatures more similar to primary human OSCCs than OSCCs in immune compromised recipient mice. Additionally, we developed genetically engineered mouse models (GEMMs) with spontaneous OSCCs. Using these complementary models, we will study the influence of the microenvironment on CSC properties, and how this alters treatment resistance. First, we will examine if immune system and species-matched stromal cells affect sizes and behaviors of transplanted CSCs, including cancer initiation, metastasis and resistance to radiation, the main therapy for OSCC. Second, we will combine CSCs in co-culture systems with primary cancer associated fibroblasts (CAFs) or CAFs from XactMice from the same patient, and assess if HSC-derived fibroblasts have the same influence as primary CAFs on CSC self-renewal and invasion, and if a small portion of HSC-derived fibroblasts among mouse fibroblasts is sufficient to contribute to CSC behavioral changes. Finally, based on our preliminary data, we will study if inhibiting TGF? signaling hampers CSC properties of cancer initiation, metastasis and radiotherapy resistance, and identify which TGF? signaling components and targets are involved in CSC regulation. Our efforts to transform human cancer models in which human OSCCs grow in immune competent and species-matched stromal cells provide an ideal platform to study the interaction between CSCs and stroma in OSCC. These experiments will advance understanding of CSC biology, tumor- stroma interactions in human cancer, and the prioritization of novel targeted molecules for inhibiting cancer growth and metastasis.