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 例 尽管 LUAD 治疗最近取得了进展，但该病的死亡率仍然很高。 因此，对于 LUAD 的新颖有效的治疗策略存在着未得到满足的关键临床需求。 癌细胞可塑性——分化和适应细胞外在压力的能力——肿瘤驱动力。 是 LUAD 治疗失败的主要原因，因此，针对 LUAD 的可塑性是一种有前途的方法。 实现靶向癌细胞可塑性的治疗潜力需要基础。 了解促进 LUAD 可塑性的细胞状态以及驱动的分子机制 使用 LUAD 基因工程小鼠模型 (GEMM) 和单细胞 mRNA 测序。 （scRNA-Seq）为了研究 LUAD 进化，我们鉴定了一种高可塑性细胞状态（HPCS），该状态是通过 HPCS 是肿瘤进化早期阶段的 LUAD 细胞的一个子集，在小鼠和小鼠体内普遍存在。 人体内 LUAD 与阶段无关，并且具有相当大的肿瘤内和肿瘤间遗传和表型 此外，HPCS 基因表达特征与特别差的患者预后相关。 前瞻性分离的 HPCS 细胞被赋予强大的分化能力（可塑性）和 增殖，并且 HPCS 在化疗后得到了极大的丰富。 支持可塑性集中在 HPCS 中，它与高增长潜力相关，并且 然而，HPCS 对 LUAD 生长、治疗耐药性的贡献或重要性， LUAD 肿瘤内新的恶性细胞状态的出现或出现尚不清楚，同样，人们对此知之甚少。 我们发现 HPCS 对于 LUAD 可塑性的进展至关重要。 LUAD 的癌前肿瘤以及 LUAD 生长、细胞状态转变和化疗耐药。 为了解决这个假设，我们将使用谱系来询问 HPCS 在 LUAD 进展和治疗抵抗中的作用 使用我们生成的新颖的报告系统进行消融和谱系追踪，我们将与 scRNA-seq。为了解决分子 HPCS 驱动因素，我们将失活或过度表达两个候选转录。 LUAD GEMM 和人类患者来源的异种移植 (PDX) LUAD 模型中的因素，其次是基因 我们提出的研究将使我们能够建立 HPCS，一个 以前未知的细胞状态，作为消除 LUAD 可塑性的关键，这将导致一种新的治疗方法。 此外，我们的工作将促进实体瘤中高可塑性细胞状态的靶向。 为体内癌症细胞状态异质性的原位研究提供了一个新的平台。