(PQ1) Progenitor cell malfunction, mutations and changes in microenvironment: A dynamic risk spectrum for cancer evolution

(PQ1) 祖细胞功能障碍、突变和微环境变化：癌症进化的动态风险谱

• 批准号: 10477027
• 负责人: Moumita Ghosh
• 金额: $ 30.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477027
• 关键词: Address; Biopsy; Bronchoscopy; Cancer Etiology; Carcinoma; Cells; Chemoprevention; Chemopreventive Agent; Cytometry; DNA Sequence Alteration; Data; Development; Dysplasia; Elements; Endothelial Cells; Epigenetic Process; Epithelial; Event; Evolution; Exhibits; FGFR1 gene; Functional disorder; Future; Genetic; Genomics; Goals; Heterogeneity; High grade dysplasia; Histologic; Iloprost; Immune; In Vitro; Incidence; Inflammation; Intervention; Lesion; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methylation; Molecular; Mutate; Mutation; Neoplasms; Pathway interactions; Patients; Preventive; Property; Recording of previous events; Risk; Site; Smoker; Somatic Mutation; Squamous Cell Lung Carcinoma; Stromal Cells; TP53 gene; Testing; Time; Work; angiogenesis; base; cancer invasiveness; cancer site; carcinogenesis; carcinogenicity; cell type; design; epithelial stem cell; exome sequencing; former smoker; genomic profiles; high risk; immune checkpoint; improved outcome; lung development; migration; mortality; novel; novel chemoprevention; novel therapeutic intervention; predictive marker; premalignant; prevent; progenitor; public health relevance; repaired; response; secondary analysis; self-renewal; single-cell RNA sequencing; smoking cessation; stem cell function; stem cells; transcriptome sequencing; tumor

Project Summary/Abstract In this proposal we will address the provocative question (PQ1): “For tumors that arise from a premalignant field, what properties of cells in this field can be used to design strategies to inhibit the development of future tumors? We will focus on squamous cell lung cancer (SCC), a common cause of cancer mortality and a neoplasm for which there is considerable evidence supporting an origin from a premalignant field. We propose to answer this question through a comprehensive strategy that focuses on three critical elements of the premalignant field for SCC of the lung: epithelial progenitor cell function, which is required for repair and maintenance of a healthy epithelium; genomic alterations in premalignant dysplasias; and the composition and function of the microenvironment. We hypothesize that “Evolution of lung cancer from a field of premalignant dysplasia is driven both by intrinsic changes in epithelial progenitor cells as well as changes that occur in the field microenvironment. Thus, therapy could be targeted to rescue functions of epithelial progenitor cells and/or to restore the microenvironment.” We propose three aims to address this hypothesis. Aim 1. Mechanisms of progenitor malfunction to identify new targets for chemoprevention: We will determine whether epithelial progenitor malfunction in terms of self-renewal and multipotentiality varies across a dysplasia spectrum. We will also assess whether progenitor response to the chemopreventive agent iloprost differs across this dysplasia spectrum. RNA sequencing will explore determinants of progenitor dysfunction and response to iloprost, potentially identifying novel interventions and predictive biomarkers. Aim 2. Detecting novel genomic changes to identify new targets for chemoprevention: We will assess whether the genetic and epigenetic profile of dysplasia varies across the above dysplasia spectrum. Brushings collected from the same dysplasia spectrum will be used to identify mutations, epigenetic alterations and transcriptomal changes; all compared to the tumor in those subjects with SCC. Targetable mutations and pathways will be identified. Aim 3. Changes in composition and function of microenvironment to identify new targets for chemoprevention: We will assess whether the microenvironment varies across the above dysplasia spectrum. Mass cytometry will be used to characterize cells that constitute the field microenvironment. We will also explore cellular heterogeneity in the field in a subset of dysplasias with known history of persistence/progression or regression using single cell transcriptomic profiling of flow-sorted epithelial and non-epithelial cells. Identification of intervention targets, such as immune checkpoints, inflammation and angiogenesis will be our goal. We anticipate that our integrative approach will lead to new strategies to prevent the evolution of premalignancy to invasive SCC.

项目总结/摘要 在本提案中，我们将解决一个挑衅性的问题（PQ 1）：“对于肿瘤， 癌前区域，该区域细胞的哪些特性可用于设计抑制癌前病变的策略。 未来肿瘤的发展？ 我们将重点关注鳞状细胞肺癌（SCC），这是癌症死亡的常见原因， 有大量证据支持起源于癌前病变的肿瘤。我们提出 通过一项全面战略来回答这个问题，该战略侧重于 肺鳞状细胞癌癌前病变：上皮祖细胞功能，这是修复和 维持健康上皮;癌前发育不良中的基因组改变;以及所述组合物 和微环境的功能。我们假设“肺癌从一个领域的演变， 癌前发育不良是由上皮祖细胞的内在变化以及 微环境发生的变化。因此，治疗可以针对拯救功能 上皮祖细胞和/或恢复微环境。”我们提出三个目标， 这个假设。目标1.祖细胞功能障碍的机制，以确定新的目标， 化学预防：我们将确定上皮祖细胞是否在自我更新方面发生功能障碍， 多潜能性在发育异常谱系中变化。我们还将评估是否祖细胞反应， 化学预防剂伊洛前列素在该发育异常谱中不同。RNA测序将探索 祖细胞功能障碍的决定因素和对伊洛前列素的反应，可能确定新的干预措施， 预测性生物标志物。目标2.检测新的基因组变化，以确定新的靶点 化学预防：我们将评估发育不良的遗传和表观遗传特征是否在不同的年龄段有所不同。 高于发育异常谱。从相同的发育异常谱系中收集的刷毛将用于识别 突变、表观遗传学改变和转录组变化;所有这些都与那些具有以下特征的受试者中的肿瘤相比： SCC。将确定靶向突变和途径。目标3。组成和职能的变化 微环境，以确定化学预防的新目标：我们将评估是否 微环境在上述发育异常谱中变化。将使用质谱细胞术表征 构成微环境的细胞。我们还将探讨细胞异质性在外地在一个 已知有单细胞法持续/进展或消退病史的发育不良亚组 流式分选的上皮细胞和非上皮细胞的转录组学分析。确定干预目标， 如免疫检查点、炎症和血管生成将是我们的目标。我们预计， 综合性的方法将导致新的策略，以防止癌前病变演变为浸润性SCC。

项目成果

Reduced Progenitor Function and Altered Immune Landscape Contribute to Field Cancerization of Lung Adenocarcinoma.

祖细胞功能降低和免疫景观改变导致肺腺癌局部癌化。

• DOI: 10.1164/rccm.202303-0585le
• 发表时间: 2023
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Assante,Alexis;Lkhagvadorj,Khosbayar;Clambey,EricT;Danhorn,Thomas;Merrick,DanielT;Keith,RobertL;New,MelissaL;Degregori,James;Miller,YorkE;Ghosh,Moumita
• 通讯作者: Ghosh,Moumita