Cancer Cell-Extrinsic and Intrinsic Regulators of Tumorigenesis

项目总结/摘要 皮肤鳞状细胞癌（cSCC）是美国第二常见的癌症， 导致大量发病，具有转移性扩散和死亡的显著风险。治疗选择有限 无法切除的病例，估计每年高达40，000例。治疗进展受阻 由于对cSCC中肿瘤内异质性（ITH）的不完全了解，特别是关于不同肿瘤 亚群在生长的肿瘤中表现。ITH可以由癌症内的细胞内在异常驱动 细胞，但越来越多的证据表明，癌细胞与不同的细胞类型，如免疫细胞， 或基质细胞，在肿瘤微环境（TME）中协调恶性行为，如侵袭。因此，在本发明中， 从TME和细胞内在的贡献中，对ITH如何在cSCC中产生的更深入的理解， 可能产生新的治疗策略。 最近发现的一种新的cSCC肿瘤细胞亚群是通过单细胞分析促进的。 患者cSCC肿瘤。这种肿瘤特异性角质形成细胞（TSK）亚群被发现表达一种基因， 在正常皮肤中不存在的特征，提示侵袭能力，并与预后不良相关 几种上皮癌的研究空间分布显示TSK位于肿瘤前缘 邻近癌症相关成纤维细胞（CAF），表明TME中这些细胞类型之间的串扰 可以控制TSK单元状态或功能。整合单细胞和空间数据的全局配体-受体分析 指定的特异性CAF衍生配体与TSK表达的受体匹配，包括几种整联蛋白。 介导TME信号的整合素信号传导基因是体内CRISPR筛选中肿瘤生长所需的， 包括ITGB 1、FERMT 1、CD 151和ARPC 2。因此，这些数据支持一种模型，其中从 邻近TSK的TME细胞通过ITGB 1介导的信号传导促进肿瘤发生和潜在的侵袭。 通过两个具体目标，这项工作将确定阻断cSCC特异性CAF衍生因子和 使癌症亚群失能的内在因素可阻碍TSK形成和随后的肿瘤侵袭， 临床前模型的进展。目的我将采用一个人类器官模型的cSCC评估的贡献， 通过基因消融和治疗性治疗， 封锁目的II将确定TSK亚群特异性因素如何合作，以促进入侵， 异种移植小鼠模型中的类器官和肿瘤发生， 因子交互作用这项工作将在医学科学家Paul Khavari博士的指导下进行 他是世界级研究机构斯坦福大学的皮肤癌遗传学专家。这些研究可以 有助于开发新的治疗策略来治疗不可切除的cSCC，并导致更深层次的分子生物学研究。 了解肿瘤侵袭、异质性和进展的途径。

PROJECT SUMMARY/ABSTRACT Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer overall in the U.S. and causes substantial morbidity, with a significant risk of metastatic spread and death. Treatment options are limited in unresectable cases, which are estimated at up to 40,000 per year. Advances in treatment have been hindered by incomplete knowledge of intratumoral heterogeneity (ITH) in cSCC, particularly regarding how different tumor subpopulations behave within a growing tumor. ITH can be driven by cell-intrinsic abnormalities within cancer cells, but increasing evidence suggests that cancer cells communicate with diverse cell types, such as immune or stromal cells, in the tumor microenvironment (TME) to coordinate malignant behavior such as invasion. Thus, a deeper understanding of how ITH arises in cSCC, from both TME and cell-intrinsic contributions, has the potential to yield new treatment strategies. Recent discovery of a novel subpopulation of cSCC tumor cells was facilitated through single-cell profiling of patient cSCC tumors. This tumor-specific keratinocyte (TSK) subpopulation was found to express a gene signature that was absent in normal skin, suggestive of invasive capacity, and associated with worse prognosis across several epithelial cancers. Spatial profiling demonstrated that TSKs resided at the tumor leading edge adjacent to cancer-associated fibroblasts (CAFs), suggesting that crosstalk among these cell types in the TME may control TSK cell state or function. Global ligand-receptor analyses integrating single-cell and spatial data nominated specific CAF-derived ligands matched with receptors expressed by TSKs, including several integrins. Integrin signaling genes mediating TME signals were required for tumor growth in CRISPR screens in vivo, including ITGB1, FERMT1, CD151, and ARPC2. Thus, these data support a model in which signals derived from TME cells proximal to TSKs promote tumorigenesis and potential invasion through ITGB1-mediated signaling. Through two specific aims, this work will determine if blocking cSCC-specific CAF-derived factors and disabling cancer subpopulation-intrinsic factors can impede TSK formation and subsequent tumor invasion and progression in preclinical models. Aim I will employ a human organoid model of cSCC to assess the contribution of CAF-derived ligands toward emergence of TSKs and invasion through genetic ablation and therapeutic blockade. Aim II will determine how TSK subpopulation-specific factors cooperate to facilitate invasion in organoids and tumorigenesis in xenograft mouse models through genetic manipulation of cancer cells to prevent factor interaction. This work will be performed under the mentorship of Dr. Paul Khavari, a physician-scientist and expert in skin cancer genetics, at Stanford University, a world-class research institution. These studies could aid the development of novel therapeutic strategies to treat unresectable cSCC and lead to a deeper molecular understanding of pathways enabling tumor invasion, heterogeneity, and progression.