Cancer Cell-Extrinsic and Intrinsic Regulators of Tumorigenesis

癌细胞-肿瘤发生的外在和内在调节因子

• 批准号: 10682445
• 负责人: Andrew Ji
• 金额: $ 21.7万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-02 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682445
• 关键词: Ablation; Affect; Antibodies; Behavior; Binding; Biochemical; CRISPR screen; Cancer cell line; Carcinoma; Cell Communication; Cell Line; Cells; Cessation of life; Communication; Data; Dermal; Development; Exhibits; Fibroblasts; Fibronectins; Genes; Genetic; Heterogeneity; Histologic; Human; Immune; Institution; Integrins; Intrinsic factor; Invaded; Knock-out; Knowledge; Ligands; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Mentorship; Minority; Modeling; Molecular; Morbidity - disease rate; Multiplexed Ion Beam Imaging; Neoplasms; Neoplastic Keratinocyte; Oncogenic; Organoids; Pathway interactions; Patients; Physicians; Pre-Clinical Model; Process; Prognosis; Recurrence; Research; Risk; Role; Scientist; Signal Transduction; Site; Skin; Skin Cancer; Stromal Cells; Stromal Invasion; Therapeutic; Tumor Cell Invasion; Tumor Promotion; United States; Universities; Unresectable; Up-Regulation; Work; Xenograft procedure; cancer cell; cancer genetics; cancer type; cell type; cohort; connective tissue growth factor; genetic manipulation; genetic signature; in vivo; keratinocyte; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; prevent; receptor; single-cell RNA sequencing; skin squamous cell carcinoma; transcriptomics; treatment strategy; tumor; tumor growth; tumor heterogeneity; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

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.

项目概要/摘要 皮肤鳞状细胞癌 (cSCC) 是美国第二大常见癌症， 导致大量发病，并具有显着的转移扩散和死亡风险。治疗选择有限 无法切除的病例估计每年高达 40,000 例。治疗进展受到阻碍 由于对 cSCC 瘤内异质性 (ITH) 的了解不完全，特别是关于不同肿瘤如何 亚群在生长的肿瘤内表现。 ITH 可能是由癌症内的细胞内在异常驱动的 细胞，但越来越多的证据表明癌细胞与不同的细胞类型进行交流，例如免疫细胞 或基质细胞，在肿瘤微环境（TME）中协调恶性行为，例如侵袭。因此， 通过 TME 和细胞内在的贡献，更深入地了解 ITH 在 cSCC 中如何产生，具有以下意义： 产生新治疗策略的潜力。 最近通过单细胞分析促进了 cSCC 肿瘤细胞的新亚群的发现 患者 cSCC 肿瘤。发现这种肿瘤特异性角质形成细胞 (TSK) 亚群表达一种基因 正常皮肤中不存在的特征，表明具有侵袭能力，并且与较差的预后相关 跨越几种上皮癌。空间分析表明 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 可能控制 TSK 细胞状态或功能。整合单细胞和空间数据的全局配体受体分析 提名的特定 CAF 衍生配体与 TSK 表达的受体（包括几种整合素）相匹配。 在体内 CRISPR 筛选中，肿瘤生长需要介导 TME 信号的整合素信号基因， 包括 ITGB1、FERMT1、CD151 和 ARPC2。因此，这些数据支持一个模型，其中信号源自 TSK 附近的 TME 细胞通过 ITGB1 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，这项工作将确定是否阻断 cSCC 特异性 CAF 衍生因子和 禁用癌症亚群的内在因素可以阻碍 TSK 的形成以及随后的肿瘤侵袭和 临床前模型的进展。目标 我将采用 cSCC 的人类类器官模型来评估贡献 通过基因消融和治疗，CAF 衍生配体的 TSK 出现和侵袭 封锁。目标 II 将确定 TSK 亚群特定因素如何合作以促进入侵 通过对癌细胞进行基因操作来预防异种移植小鼠模型中的类器官和肿瘤发生 因素相互作用。这项工作将在医学科学家 Paul Khavari 博士的指导下进行 世界一流研究机构斯坦福大学皮肤癌遗传学专家。这些研究可以 帮助开发新的治疗策略来治疗不可切除的鳞状细胞癌，并导致更深入的分子研究 了解肿瘤侵袭、异质性和进展的途径。

项目成果

STmut: a framework for visualizing somatic alterations in spatial transcriptomics data of cancer.

• DOI: 10.1186/s13059-023-03121-6
• 发表时间: 2023-11-30
• 期刊: Genome biology
• 影响因子: 12.3

Research Techniques Made Simple: Spatial Transcriptomics.

• DOI: 10.1016/j.jid.2021.12.014
• 发表时间: 2022-04
• 期刊: The Journal of investigative dermatology
• 作者: Piñeiro AJ;Houser AE;Ji AL
• 通讯作者: Ji AL

Spatially resolved clonal copy number alterations in benign and malignant tissue.

• DOI: 10.1038/s41586-022-05023-2
• 发表时间: 2022-08
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Erickson, Andrew;He, Mengxiao;Berglund, Emelie;Marklund, Maja;Mirzazadeh, Reza;Schultz, Niklas;Kvastad, Linda;Andersson, Alma;Bergenstrahle, Ludvig;Bergenstrahle, Joseph;Larsson, Ludvig;Galicia, Leire Alonso;Shamikh, Alia;Basmaci, Elisa;De Stahl, Teresita Diaz;Rajakumar, Timothy;Doultsinos, Dimitrios;Thrane, Kim;Ji, Andrew L.;Khavari, Paul A.;Tarish, Firaz;Tanoglidi, Anna;Maaskola, Jonas;Colling, Richard;Mirtti, Tuomas;Hamdy, Freddie C.;Woodcock, Dan J.;Helleday, Thomas;Mills, Ian G.;Lamb, Alastair D.;Lundeberg, Joakim
• 通讯作者: Lundeberg, Joakim

The Use of Single-Cell RNA-Sequencing and Spatial Transcriptomics in Understanding the Pathogenesis and Treatment of Skin Diseases.

• DOI: 10.1016/j.xjidi.2023.100198
• 发表时间: 2023-07
• 期刊: JID innovations : skin science from molecules to population health
• 作者: Houser, Aubrey E;Kazmi, Abiha;Nair, Arjun K;Ji, Andrew L
• 通讯作者: Ji, Andrew L