Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity

胰腺癌恶性细胞状态的基质调节和治疗敏感性

• 批准号: 10706519
• 负责人: Andrew James Aguirre
• 金额: $ 103.7万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706519
• 关键词: Adjuvant Study; Affect; Aftercare; Antibodies; Archives; Biology; Biopsy; Cell Communication; Cells; Cellular Structures; Clinical; Clinical Trials; Coculture Techniques; Complex; Data; Dermal; Disease Progression; Disease Resistance; Evolution; Exhibits; Fibroblasts; Gene Expression; Genetic Screening; Genetically Engineered Mouse; Genomic approach; Growth Factor; Heterogeneity; Human; Hypoxia; Immunofluorescence Immunologic; Impairment; Investigation; Isogenic transplantation; Ligands; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Mesenchymal; Metastatic Neoplasm to the Liver; Modeling; Nature; Neoadjuvant Therapy; Neoplasm Metastasis; Nutrient; Organ; Organoids; Pancreatic Ductal Adenocarcinoma; Patients; Pattern; Pericytes; Pharmaceutical Preparations; Phenotype; Play; Population; Prior Therapy; Process; Protein Secretion; Resistance; Role; Sampling; Shapes; Signal Transduction; Specimen; Stromal Cells; TGFB1 gene; Testing; Therapeutic; Tumor Subtype; Work; biobank; cancer cell; cell type; chemotherapy; cytokine; differential expression; digital; functional genomics; innovation; insight; member; multidisciplinary; neoplastic cell; novel; novel strategies; novel therapeutic intervention; programs; response; single nucleus RNA-sequencing; single-cell RNA sequencing; standard of care; therapeutic target; therapy resistant; transcriptome; translational scientist; transplant model; treatment response; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

Abstract Unlike many cancers, pancreatic ductal adenocarcinoma (PDAC) is characterized by a hypoxic, nutrient- deprived, immunosuppressive tumor microenvironment (TME) and a fibrotic stroma that may impair treatment response. Recent single-cell studies suggest a complex interplay between malignant tumor cells and other cell types within the TME, with crosstalk between tumor and stromal cell types influencing malignant cell phenotypes, including responses to therapy. Understanding these interactions will provide insight into PDAC progression and therapy resistance. In particular, cancer-associated fibroblasts (CAFs) are a major non-immune cell component of the TME and are comprised of several distinct subtypes that vary based on tumor subtype and the surrounding microenvironmental niche. In this proposal, we bring together a multidisciplinary team of basic and translational investigators that will build upon our prior studies to investigate the Tumor-TME co-organizer model with a focus on interrogating interactions between PDAC tumor cells and CAFs in the TME. Specifically, we will examine the overarching hypothesis that reciprocal signaling between tumor cells and CAFs shapes malignant cell and CAF phenotypes in a context-specific manner that can be modulated by prior therapy and the organ-specific niche. We will leverage multiple built-in capabilities, including genetically engineered mouse models (GEMMs), patient- derived organoid (PDO) and matched fibroblast models, functional genetic screens and clinical trials with serial biopsies to study the PDAC TME continuum in disease progression and resistance to therapy. Specifically, we propose (1) to determine whether targeting organ-specific PDAC-CAF interactions enhances therapeutic responses, (2) to interrogate novel vulnerabilities resulting from tumor cell and CAF reprogramming during PDAC therapy, and (3) investigate whether TGFB blockade disrupts tumor cell-CAF crosstalk and sensitizes PDAC to chemotherapy. In pursuing these studies, we will work with other members of the PDAC Stromal Reprogramming Consortium (PSRC) to pursue collaborative studies to understand how PDAC and TME interactions program tumor progression and therapy responses.

摘要 与许多癌症不同，胰腺导管腺癌(PDAC)的特点是低氧、营养- 缺乏免疫抑制的肿瘤微环境(TME)和可能影响治疗的纤维化间质 回应。最近的单细胞研究表明，恶性肿瘤细胞和其他细胞之间存在复杂的相互作用 TME内的类型，肿瘤和间质细胞类型之间的串扰影响恶性细胞表型， 包括对治疗的反应。了解这些交互作用将有助于深入了解PDAC的进展和 治疗抵抗。 特别是，癌症相关成纤维细胞(CAF)是TME的主要非免疫细胞成分，是 由几种不同的亚型组成，根据肿瘤亚型和周围环境的不同而有所不同 微环境利基。在这项提议中，我们汇集了一个由基础和翻译组成的多学科团队 研究人员将在我们先前研究的基础上，重点研究肿瘤-TME联合组织者模型 TME中PDAC肿瘤细胞与CAF相互作用的研究。具体来说，我们将研究 肿瘤细胞和CAF之间的相互信号形成恶性细胞和CAF的首要假设 表型以特定于背景的方式进行，可以通过先前的治疗和特定器官的利基来调节。 我们将利用多种内置功能，包括基因工程小鼠模型(GEM)、患者- 衍生有机化合物(PDO)和配对成纤维细胞模型、功能遗传筛选和临床系列试验 活检以研究PDAC TME连续体在疾病进展和治疗耐药中的作用。具体来说，我们 建议(1)确定靶向器官特异性PDAC-CAF相互作用是否增强治疗 响应，(2)询问PDAC期间肿瘤细胞和CAF重新编程导致的新脆弱性 治疗，以及(3)研究TGFb阻断是否扰乱肿瘤细胞-CAF串扰并使PDAC对 化疗。在进行这些研究时，我们将与PDAC基质重新编程的其他成员合作 财团(PSRC)将进行协作研究，以了解PDAC和TME的互动计划 肿瘤进展和治疗反应。