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)由于进展迅速，仍然是最致命的癌症之一， 对治疗的抵抗力，以及高转移率。转移的常见部位是腹膜。 空洞发生在40-50%的患者中，并导致腹膜癌病(PC)的发展。个人电脑是 几乎是一种普遍的致命诊断，由于治疗选择有限，生存时间不到6个月 目前都是可用的。肿瘤内异质性(ITH)是GAC的一个基本特征，有助于 治疗抵抗、疾病进展和转移。我们和其他人已经描述了基因组和 GAC和PC中的分子ITH，然而，肿瘤细胞谱系可塑性−是ITH的非遗传、细胞内在起源 人们对此仍然知之甚少。在我们利用单细胞解剖细胞和分子ITH的初步努力中 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的 PC的表型ITH的关键调节因子，超越了遗传因素。我们还发现，根据以下因素分类的肿瘤 肿瘤细胞谱系/状态组成(细胞亚型)与生存密切相关，表现为 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/状态动态演变以抵抗治疗并促进肿瘤生长及其成分 决定GAC的表型和结局。目标1的目标是表征肿瘤细胞谱系/状态 临床确定的GAC队列中的多样性和组成决定了它们对肿瘤细胞克隆的影响 与GAC进展和转移相关的进化和身份谱系特征。我们还将介绍 成对基线肿瘤和进展期肿瘤化疗后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 治疗，并确定与治疗抵抗相关的谱系特征。在目标2中，我们将利用我们的 GAC的基因工程小鼠模型(GEMM)跟随癌症的扩展和扩散 GEMM中的细胞在一段时间内纵向跟踪和表征肿瘤细胞的动态变化 单细胞分辨率下的谱系身份和转录组状态。我们将研究克隆性建筑 不同谱系/状态的肿瘤细胞，并检测支持肿瘤的克隆群体的动态 在原发部位的生长，种子和定植远处的器官；我们也将描述肿瘤细胞如何在不同的 在原发肿瘤部位，血统与时间相互作用，影响肿瘤的侵袭和扩散。在目标3中，我们 将研究GEMM中肿瘤细胞系的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，并确定基本的 世系/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。更好地了解表型来源 GAC进展背后的异质性和动力学对于确定有效的治疗方法至关重要。