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: 10662203
• 负责人: Pawel K. Mazur
• 金额: $ 62.94万
• 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/10662203
• 关键词: Aggressive behavior; Architecture; Behavior; Biology; Cancer Biology; Carcinomatosis; Cell Lineage; Cells; Classification; 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; Invaded; Link; Malignant Neoplasms; Measures; Medicine; Modeling; Molecular; Nature; Neoplasm Metastasis; Oncogenic; Organ; Outcome; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Peritoneal; Phenotype; Population; Population Dynamics; Primary Neoplasm; Process; Property; Recurrence; Research; Resistance; Resolution; Risk; Role; Sampling; Signal Pathway; Site; Source; System; Therapeutic; Time; Treatment Failure; Tumor Cell Invasion; Tumor Promotion; Tumor-infiltrating immune cells; anti-PD1 therapy; cancer cell; cancer therapy; cell behavior; chemotherapy; cohort; effective therapy; improved; in vivo; malignant stomach neoplasm; mouse model; neoplastic cell; non-genetic; novel; patient response; pharmacologic; 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）由于其快速进展而仍然是最致命的癌症形式之一， 对治疗的抵抗力和高转移扩散率。常见的转移部位是腹膜 在40-50%的患者中发生的空洞，导致腹膜癌病（PC）的发展。PC是 几乎是一种普遍致命的诊断，由于治疗选择有限， 目前可用。肿瘤内异质性（ITH）是GAC的基本性质，有助于 治疗抗性、疾病进展和转移。我们和其他人已经描述了基因组和 然而，肿瘤细胞谱系可塑性-ITH的非遗传性，细胞内在起源 仍然知之甚少。在我们初步尝试使用单细胞免疫组织化学技术来分析ITH的细胞和分子结构时， 分析，我们发现肿瘤细胞谱系/状态组成的多样性似乎是一个上游， PC表型ITH的关键调节因子，超出遗传因素。我们还发现，肿瘤分类的基础上 肿瘤细胞谱系/状态组成（细胞亚型）与存活率密切相关， 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/状态动态进化以抵抗治疗并促进肿瘤生长及其组成 决定了GACs的表型和结果。目标1的目标是表征肿瘤细胞谱系/状态 临床定义的GAC队列的多样性和组成，确定它们对肿瘤细胞克隆形成的影响。 进化和与GAC进展和转移相关的身份谱系特征。我们还将分析 化疗后配对基线和进展性肿瘤中肿瘤细胞谱系和状态的变化 或免疫疗法，确定它们对免疫表型和患者对抗癌反应的影响 治疗，并确定与耐药性相关的谱系特征。在目标2中，我们将利用 GAC的基因工程小鼠模型（GEMM），跟踪癌症的扩展和传播， 在一段时间内在GEMM中的细胞中纵向跟踪和表征肿瘤细胞中的动态变化 谱系身份和转录组状态在单细胞分辨率。我们将研究的克隆结构 不同谱系/状态的肿瘤细胞，并检查维持肿瘤的克隆群体的动态 在原发部位生长，播种和定植远端器官;我们还将分析肿瘤细胞如何在不同的组织中生长， 谱系在原发肿瘤部位与TIME相互作用并影响侵袭和扩散。在目标3中，我们 将研究肿瘤细胞谱系可塑性对化疗和免疫治疗的反应。我们 将表征治疗诱导的耐药细胞谱系/状态的出现，并确定 谱系/状态转换的途径和驱动因素。这项研究将肿瘤细胞谱系/状态可塑性与GAC联系起来 治疗抗性、进展和转移。更好地理解表型的来源 GAC进展的异质性和动力学对于确定有效的治疗至关重要。