Targeting plasticity in lung cancer

针对肺癌的可塑性

• 批准号: 10587251
• 负责人: Tuomas Tammela
• 金额: $ 58.38万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587251
• 关键词: Ablation; Address; Adenocarcinoma Cell; Biological Assay; CRISPR/Cas technology; Cells; Cessation of life; Chemoresistance; Chromatin; Clinical; Data; Differentiation and Growth; Disease; Dose; Endowment; Evolution; Future; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genotype; Growth; Heterogeneity; Human; In Situ; Investigation; Knowledge; Lesion; Lung Adenocarcinoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Methods; Modeling; Molecular; Molecular Target; Mus; Neoplasms; Non-Small-Cell Lung Carcinoma; Patient-Focused Outcomes; Patients; Phenotype; Proliferating; Reporter; Resolution; Role; Solid Neoplasm; System; Testing; Therapeutic; Transplantation; Treatment Failure; Tumor stage; Work; bioluminescence imaging; cDNA Expression; cancer cell; candidate identification; chemotherapy; experimental study; gain of function; in vivo; loss of function; novel; novel therapeutics; overexpression; patient derived xenograft model; premalignant; pressure; programs; prospective; response; single cell mRNA sequencing; single-cell RNA sequencing; small hairpin RNA; therapeutically effective; therapy resistant; transcription factor; transcriptome sequencing; tumor; tumor progression

SUMMARY Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, results in ~55,000 deaths in the US every year. Despite the recent advancements in LUAD treatment, the disease remains highly intractable. Thus, a critical unmet clinical need exists for novel and effective therapeutic strategies for LUAD patients. Cancer cell plasticity – the capacity to differentiate and adapt to cell-extrinsic pressure – drives tumor progression and is a major cause of treatment failure in LUAD. Thus, targeting plasticity in LUAD is a promising therapeutic concept. Realizing the therapeutic potential of targeting cancer cell plasticity requires fundamental understanding of the cell states that promote plasticity in LUAD as well as the molecular mechanisms that drive them. Using a genetically engineered mouse model (GEMM) of LUAD and single-cell mRNA sequencing (scRNA-Seq) to investigate LUAD evolution we identified a high-plasticity cell state (HPCS) that is acquired by a subset of LUAD cells in early stages of tumor evolution. The HPCS was ubiquitously maintained in mouse and human LUAD in vivo irrespective of stage and considerable intra- and inter-tumoral genetic and phenotypic diversity. Further, the HPCS gene expression signature correlated with particularly poor patient outcomes. Prospectively isolated HPCS cells were endowed with robust capacity for differentiation (plasticity) and proliferation, and the HPCS was strongly enriched following chemotherapy. Our preliminary work strongly supports plasticity is concentrated in the HPCS and that it is associated with high growth potential and chemoresistance. However, the contribution or essentiality of the HPCS for LUAD growth, treatment resistance, or emergence of new malignant cell states within LUAD tumors is not known. Similarly, little is known of the transcriptional drivers of LUAD plasticity. We hypothesize that the HPCS is essential for progression of premalignant neoplasias to LUAD as well as for LUAD growth, cell state transitions, and chemoresistance. To address this hypothesis, we will interrogate HPCS in LUAD progression and treatment resistance using lineage- ablation and lineage-tracing using a novel reporter system that we have generated, which we will combine with scRNA-seq. To address molecular HPCS drivers, we will inactivate or overexpress two candidate transcription factors in the LUAD GEMM and in human patient-derived xenograft (PDX) LUAD models, followed by gene expression and chromatin accessibility profiling. Our proposed study will allow us to establish the HPCS, a previously unknown cell state, as key to eradicating plasticity in LUAD. This would lead to a new treatment paradigm, motivating targeting of high-plasticity cell states across solid tumors. Furthermore, our work will contribute a novel platform for the in situ investigation of cell state heterogeneity in cancers in vivo.

总结 肺腺癌（LUAD）是非小细胞肺癌最常见的亚型， 美国每年的死亡人数。尽管最近LUAD治疗取得了进展，但该疾病仍然高度流行。 难对付因此，对于LUAD的新的和有效的治疗策略存在关键的未满足的临床需求 患者癌细胞可塑性-分化和适应细胞外部压力的能力-驱动肿瘤 是LUAD治疗失败的主要原因。因此，LUAD中的靶向可塑性是一种有前途的方法。 治疗概念实现靶向癌细胞可塑性的治疗潜力需要基本的 了解促进LUAD可塑性的细胞状态以及驱动LUAD的分子机制。 他们使用LUAD的基因工程小鼠模型（GEMM）和单细胞mRNA测序 为了研究LUAD的进化，我们鉴定了一种高可塑性细胞状态（HPCS）， LUAD细胞的一个子集在肿瘤发展的早期阶段。HPCS在小鼠中普遍维持， 人LUAD在体内不考虑阶段和相当大的肿瘤内和肿瘤间遗传和表型 多样性此外，HPCS基因表达特征与特别差的患者结果相关。 Proximal分离的HPCS细胞具有强大的分化能力（可塑性）， 增殖，并且化疗后HPCS强烈富集。我们的前期工作 支持塑性集中在HPCS，它与高增长潜力， 化学抗性然而，HPCS对LUAD生长、处理抗性、 或在LUAD肿瘤中出现新的恶性细胞状态尚不清楚。同样， LUAD可塑性的转录驱动因子。我们假设HPCS对疾病的进展至关重要。 癌前肿瘤对LUAD以及LUAD生长、细胞状态转变和化学抗性的影响。到 为了解决这一假设，我们将使用谱系- 消融和谱系追踪使用一种新的报告系统，我们已经产生，我们将联合收割机， scRNA-seq.为了解决分子HPCS驱动因素，我们将使两个候选转录因子过量或过表达， 在LUAD GEMM和人类患者来源的异种移植物（PDX）LUAD模型中， 表达和染色质可及性分析。我们建议的研究将使我们能够建立健康保障计划， 以前未知的细胞状态，作为消除LUAD可塑性的关键。这将带来一种新的治疗方法 范例，激励靶向实体瘤中的高可塑性细胞状态。此外，我们的工作将 为在体内原位研究癌症中的细胞状态异质性提供了一个新的平台。