Cancer Cell-Extrinsic and Intrinsic Regulators of Tumorigenesis

项目摘要/摘要 皮肤鳞状细胞癌(CSCC)是美国第二常见的癌症， 导致相当大的发病率，有很大的转移扩散和死亡风险。治疗选择有限 在无法切除的病例中，估计每年高达40,000例。治疗方面的进展受到了阻碍 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 亚群在不断生长的肿瘤中表现出来。癌症中的细胞固有异常可能会导致ITS 细胞，但越来越多的证据表明，癌细胞与不同类型的细胞沟通，如免疫 或基质细胞，在肿瘤微环境(TME)中协调侵袭等恶性行为。因此， 更深入地了解ITH是如何从TME和细胞内在贡献中在CSCC中产生的，有 有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图谱促进的 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征象，暗示有侵袭能力，并与较差的预后有关 跨越了几种上皮性癌症。空间分布显示tsk位于肿瘤前沿。 与癌症相关成纤维细胞(CAF)相邻，表明TME中这些细胞类型之间存在串扰 可以控制TSK小区状态或功能。整合单细胞和空间数据的全球配基-受体分析 提名与TSKs表达的受体相匹配的特定CAF衍生配体，包括几个整合素。 整合素信号基因介导TME信号是CRISPR筛查体内肿瘤生长所必需的， 包括ITGB1、FERMT1、CD151和ARPC2。因此，这些数据支持这样一种模型，在该模型中信号从 TKs近端的TME细胞通过ITGB1介导的信号转导促进肿瘤的发生和潜在的侵袭。 通过两个具体的目标，这项工作将确定是否阻断CSCC特异性CAF衍生因子和 使癌症亚群失活的内在因素可以阻止TSK的形成和随后的肿瘤侵袭 临床前模型研究进展。目的我将使用CSCC的人体器官模型来评估其贡献。 CAF来源的配体通过基因消融和治疗对TSK的出现和侵袭的影响 封锁。AIM II将确定TSK亚群特有的因素如何合作促进入侵 通过对肿瘤细胞的遗传操作来预防有机物与异种移植小鼠模型的肿瘤发生 因素交互作用。这项工作将在内科科学家保罗·哈瓦里博士的指导下进行 他是世界级研究机构斯坦福大学的皮肤癌遗传学专家。这些研究可能 帮助开发新的治疗策略来治疗不能切除的CSCC并导致更深层次的分子 了解促进肿瘤侵袭、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.