Tumor cell lineage diversity and composition in gastric cancer progression and therapy resistance

胃癌进展和治疗耐药中的肿瘤细胞谱系多样性和组成

• 批准号: 10342536
• 负责人: Pawel K. Mazur
• 金额: $ 64.23万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10342536
• 关键词: Address; Aggressive behavior; Architecture; Behavior; Biology; Cancer Biology; Carcinomatosis; Cell Lineage; Cells; Clinical; Clonal Evolution; Complex; Computer Models; Data; Development; Diagnosis; Disease Progression; Distal; Distant; Ecosystem; Ensure; Evolution; Exhibits; Feedback; Gastric Adenocarcinoma; Genetic; Genetically Engineered Mouse; Genomics; Genotype; Goals; Greater sac of peritoneum; Growth; Health; Heterogeneity; Human; Immune; Immunotherapy; Link; Malignant Neoplasms; Measures; Medicine; Modeling; Molecular; Nature; Neoplasm Metastasis; Oncogenic; Organ; Outcome; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Peritoneal; Pharmacology; Phenotype; Population; Population Dynamics; Primary Neoplasm; Process; Property; Recurrence; Research; Resistance; Resolution; Risk; Role; Sampling; Seeds; Signal Pathway; Site; Source; System; Therapeutic; Time; Treatment Failure; Tumor Cell Invasion; anti-PD-1; base; cancer cell; cancer therapy; cell behavior; chemotherapy; cohort; effective therapy; improved; in vivo; malignant stomach neoplasm; molecular phenotype; mouse model; neoplastic cell; non-genetic; novel; patient response; response; single cell analysis; standard of care; therapy resistant; transcriptome; transcriptomics; tumor; tumor growth; tumor heterogeneity; tumor progression; tumor-immune system interactions

Gastric adenocarcinoma (GAC) remains one of the deadliest forms of cancer due to its rapid progression, resistance to therapy, and a high rate of metastatic spread. A common site of metastases is the peritoneal cavity that occurs in 40-50% of patients and leads to development of peritoneal carcinomatosis (PC). PC is almost a universally lethal diagnosis with survival of less than 6 months due to limited therapeutic options that are currently available. Intratumoral heterogeneity (ITH) is a fundamental property of GAC that contributes to therapy resistance, disease progression and metastasis. We and others have characterized the genomic and molecular ITH in GAC and PC, however, tumor cell lineage plasticity−the non-genetic, cell intrinsic origin of ITH remains poorly understood. In our preliminary efforts to dissect the cellular and molecular ITH using single-cell analysis, we discovered that the diversity in tumor cell lineage/state compositions appears to be an upstream key regulator of phenotypic ITH of PC, beyond the genetic factors. We also find that tumors classified based on tumor cell lineage/state compositions (cellular subtypes) are strongly associated with survival, exhibiting differential activation of oncogenic pathways and distinct immune phenotypes. We therefore hypothesize that tumor cell lineages/states dynamically evolve to resist treatment and promote tumor growth and its composition determines phenotypes and outcomes of GACs. The goal of Aim 1 is to characterize tumor cell lineage/state diversity and compositions in clinically defined GAC cohorts, determine their impacts on tumor cell clonal evolution, and identity lineage features associated with GAC progression and metastasis. We will also profile changes in tumor cell lineages and states in paired baseline and progressive tumors following chemotherapy or immunotherapy, determine their impact on immune phenotypes and patient responses to anti-cancer therapies, and identify lineage features associated with therapy resistance. In Aim 2, we will leverage our genetically engineered mouse models (GEMMs) of GAC, follow the expansion and dissemination of cancer cells in GEMMs over a period of time to longitudinally track and characterize dynamic changes in tumor cell lineage identity and transcriptome states at single-cell resolution. We will investigate the clonal architecture of tumor cells in different lineages/states and examine the dynamics of clonal populations that sustain tumor growth at the primary sites, seed and colonize distant organs; we will also profile how tumor cells in different lineages interact with TIME at the primary tumor site and influence invasion and dissemination. In Aim 3, we will investigate tumor cell lineage plasticity in response to chemotherapy and immunotherapy in GEMMs. We will characterize therapy-induced emergence of resistant cell lineages/states and identify the fundamental pathways and drivers of lineage/state transition. This study will link tumor cell lineage/state plasticity to GAC therapy resistance, progression, and metastasis. A better understanding of sources of phenotype heterogeneity and dynamics underlying GAC progression is paramount to identifying effective treatments.

胃腺癌（GAC）仍然是由于其快速发展而成为最致命的癌症之一， 对治疗的抵抗力和高转移性差异。转移的常见部位是腹膜 在40-50％的患者中发生的腔体导致腹膜癌（PC）的发展。 PC是 由于治疗选择有限，几乎是一个普遍致命的诊断，生存期少于6个月 目前可用。肿瘤内异质性（ITH）是GAC的基本特性，有助于 治疗耐药性，疾病进展和转移。我们和其他人都表征了基因组和 然而，GAC和PC中的分子ITH，肿瘤细胞谱系可塑性 - 非遗传，细胞的内在起源 仍然很了解。在我们的初步努力中，使用单细胞剖析细胞和分子ITH 分析，我们发现肿瘤细胞谱系/状态组成的多样性似乎是上游 PC的表型ITH的关键调节剂，超出了遗传因素。我们还发现肿瘤根据 肿瘤细胞谱系/状态组成（细胞亚型）与生存密切相关，表现出 致癌途径的差异激活和不同的免疫表型。因此，我们假设 肿瘤细胞谱系/状态动态发展以抵抗治疗和促进肿瘤生长及其组成 确定GAC的表型和结果。目标1的目的是表征肿瘤细胞谱系/状态 临床定义的GAC队列中的多样性和组成，确定它们对肿瘤细胞克隆的影响 进化以及与GAC进展和转移相关的身份谱系特征。我们还将配置 化疗后，肿瘤细胞谱系和配对基线和进行性肿瘤的状态的变化 或免疫疗法，确定其对免疫表型的影响以及患者对抗癌的反应 疗法并确定与治疗耐药性相关的谱系特征。在AIM 2中，我们将利用我们的 GAC的基因工程小鼠模型（GEMM），遵循癌症的扩张和传播 在一段时间内，宝石中的细胞纵向跟踪和表征肿瘤细胞的动态变化 谱系身份和单细胞分辨率的转录组状态。我们将研究克隆建筑 不同谱系/状态中的肿瘤细胞，并检查维持肿瘤的克隆种群的动力学 在初级部位生长，种子和定居遥远的器官；我们还将介绍不同的肿瘤细胞 谱系与原发性肿瘤部位的时间相互作用，并影响入侵和传播。在AIM 3中，我们 将研究肿瘤细胞谱系可响应GEMMS的化学疗法和免疫疗法的可塑性。我们 将表征治疗引起的抗性细胞谱系/状态的出现，并确定基本 谱系/状态过渡的途径和驱动因素。这项研究将将肿瘤细胞谱系/状态可塑性与GAC联系起来 治疗耐药性，进展和转移。对表型来源的更好理解 GAC进展为基础的异质性和动力学对于识别有效的治疗至关重要。