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.

由于进展迅速，胃腺癌（GAC）仍然是最致命的癌症之一， 对治疗有抵抗力，并且转移扩散率高。转移瘤的常见部位是腹膜 40-50% 的患者会出现空腔，并导致腹膜癌病 (PC) 的发展。电脑是 由于治疗选择有限，几乎是普遍致命的诊断，生存期不到 6 个月 目前可用。瘤内异质性 (ITH) 是 GAC 的一个基本特性，有助于 治疗抵抗、疾病进展和转移。我们和其他人已经表征了基因组和 然而，GAC和PC中的分子ITH，肿瘤细胞谱系可塑性——ITH的非遗传性细胞内在起源 仍然知之甚少。在我们使用单细胞剖析细胞和分子 ITH 的初步努力中 分析中，我们发现肿瘤细胞谱系/状态组成的多样性似乎是上游 PC表型ITH的关键调节因子，超越遗传因素。我们还发现肿瘤分类依据 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/状态动态进化以抵抗治疗并促进肿瘤生长及其组成 决定 GAC 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。我们还将简介 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抗癌反应的影响 疗法，并确定与治疗耐药性相关的谱系特征。在目标 2 中，我们将利用我们的 GAC 基因工程小鼠模型 (GEMM) 追踪癌症的扩展和传播 在一段时间内对 GEMM 中的细胞进行纵向跟踪和表征肿瘤细胞的动态变化 单细胞分辨率的谱系身份和转录组状态。我们将研究克隆结构 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，播种并定植远处器官；我们还将描述肿瘤细胞如何在不同的 谱系与原发肿瘤部位的 TIME 相互作用并影响侵袭和扩散。在目标 3 中，我们 将研究 GEMM 中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，并确定基本原理 谱系/状态转变的途径和驱动因素。这项研究将肿瘤细胞谱系/状态可塑性与 GAC 联系起来 治疗抵抗、进展和转移。更好地了解表型的来源 GAC 进展的异质性和动态对于确定有效的治疗方法至关重要。