Identifying oral cancer stem cell properties affected by the microenvironment

描述（由申请人提供）：预期来自口腔鳞状细胞癌（OSCC）的癌症干细胞（CSC）具有自我更新、转移和治疗抗性的特性。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，其不能捕获所有CSC特性。我们开发了“XactMice”，其中将人OSCC移植到携带人造血干细胞（HSC）的小鼠中，所述造血干细胞重建人免疫细胞和其他HSC衍生的人基质细胞。与免疫受损受体小鼠中的OSCC相比，Xact小鼠中的OSCC表现出与原代人OSCC更相似的病理和分子特征。此外，我们开发了具有自发性OSCC的基因工程小鼠模型（GEMM）。使用这些互补的模型，我们将研究微环境对CSC特性的影响，以及这如何改变治疗阻力。首先，我们将研究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，包括癌症的发生，转移和对辐射的抵抗，这是OSCC的主要治疗方法。第二，我们将在共培养系统中将联合收割机CSC与来自同一患者的原发性癌症相关成纤维细胞（CAF）或XactMice的CAF组合，并评估HSC衍生的成纤维细胞是否与原发性CAF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的一小部分HSC衍生的成纤维细胞是否足以促成CSC行为变化。最后，根据我们的初步数据，我们将研究是否抑制TGF？信号阻碍CSC的性质，癌症的起始，转移和放射治疗的阻力，并确定哪些TGF？信号传导组分和靶参与CSC调节。我们努力改造人类癌症模型，其中人类OSCC在免疫活性和物种匹配的基质细胞中生长，为研究OSCC中CSC和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、人类癌症中的肿瘤-基质相互作用以及用于抑制癌症生长和转移的新型靶向分子的优先化的理解。

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.