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.

概括 肺腺癌（LUAD）是非小细胞肺癌最常见的亚型，导致约55,000 每年在美国死亡。尽管最近在LUAD治疗方面取得了进步，但该疾病仍然很高 棘手。这是针对新颖有效的LUAD治疗策略的关键未满足的临床需求 患者。癌细胞的可塑性 - 分化和适应细胞超支压力的能力 - 驱动肿瘤 进展，是LUAD治疗失败的主要原因。那是一个承诺的靶向可塑性 治疗概念。意识到靶向癌细胞可塑性的治疗潜力需要基本 了解促进LUAD可塑性以及驱动分子机制的细胞状态 他们。使用LUAD和单细胞mRNA测序的一般设计的小鼠模型（GEMM） （SCRNA-SEQ）为了研究LUAD进化，我们确定了一个高塑性细胞态（HPC） 在肿瘤进化的早期，LUAD细胞的子集。 HPC被普遍存在在鼠标和 人体luad在体内不论阶段和考虑性内和肿瘤间遗传和表型 多样性。此外，HPCS基因表达签名与特别差的患者结局相关。 前瞻性隔离的HPC细胞具有强大的分化能力（可塑性）和 化疗后增殖，HPC强烈富集。我们的初步工作很强烈 支持可塑性集中在HPC中，它与高生长潜力和 化学抗性。但是，HPC对LUAD生长，治疗耐药性的贡献或重要性， 或尚不清楚LUAD肿瘤内新恶性细胞状态的出现。同样，对 LUAD可塑性的转录驱动器。我们假设HPC对于进展至关重要 对LUAD的肿瘤和LUAD生长，细胞状态过渡和化学抗性。到 解决这一假设，我们将使用谱系 - 使用我们已经生成的新闻记者系统的消融和谱系追踪，我们将与之结合 scrna-seq。为了解决分子HPCS驱动器，我们将灭活或过表达两个候选转录 LUAD GEMM和人类患者衍生异种移植（PDX）LUAD模型的因素，其次是基因 表达和染色质可及性分析。我们提出的研究将使我们能够建立HPC，一个 以前未知的细胞状态，是消除luad可塑性的关键。这将导致新的治疗 范式，激励靶向高塑性细胞状态跨实体瘤。此外，我们的工作将 为体内癌症的细胞状态异质性的原位研究提供了一个新的平台。