Identifying oral cancer stem cell properties affected by the microenvironment

描述(申请人提供)：口腔鳞状细胞癌(OSCCs)中的癌症干细胞(CSCs)被认为具有自我更新、转移和治疗耐药的特性。目前用于研究CSC的模型系统大多处于免疫受损和物种不匹配的基质环境中，这并不能捕捉到CSC的所有特性。我们已经开发出“XactMice”，将人的口腔鳞状细胞移植到含有人造血干细胞(HSC)的小鼠体内，HSC重建人类免疫细胞和其他HSC来源的人类基质细胞。XactMice中的口腔鳞状细胞表现出更类似于原发人类口腔鳞状细胞的病理和分子特征，而不是免疫受损受体小鼠中的口腔鳞状细胞。此外，我们开发了具有自发口腔鳞状细胞的基因工程小鼠模型(GEMM)。利用这些互补的模型，我们将研究微环境对CSC性能的影响，以及这如何改变治疗抗性。首先，我们将检查免疫系统和物种匹配的基质细胞是否会影响移植的CSCs的大小和行为，包括癌症的启动、转移和对辐射的抵抗，这是口腔鳞癌的主要治疗方法。其次，我们将在共培养系统中将CSC与来自同一患者的原代肿瘤相关成纤维细胞(CAF)或来自XactMice的CAF相结合，并评估HSC来源的成纤维细胞是否与原始CAF对CSC的自我更新和侵袭具有相同的影响，以及小鼠成纤维细胞中的一小部分HSC来源的成纤维细胞是否足以促进CSC的行为变化。最后，基于我们的初步数据，我们将研究是否抑制转化生长因子？信号转导抑制肿瘤起始、转移和放疗抵抗的CSC特性，并确定哪种转化生长因子？信号元件和靶点参与CSC的调控。我们致力于改变人类肿瘤模型，在该模型中，人类口腔鳞状细胞生长在免疫活性和物种匹配的基质细胞中，这为研究口腔鳞状细胞癌中肿瘤干细胞与基质之间的相互作用提供了理想的平台。这些实验将促进对CSC生物学、人类癌症中肿瘤-间质相互作用的理解，并优先选择新的靶向分子来抑制癌症的生长和转移。

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.