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: 10517569
• 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/10517569
• 关键词: Affect; Aftercare; Antibodies; Archives; Biology; Biopsy; Cell Nucleus; 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; Light; 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; Proteins; Resistance; Role; Sampling; Shapes; Signal Transduction; Small Nuclear RNA; Specimen; Stromal Cells; TGFB1 gene; Testing; Therapeutic; Tumor Subtype; Work; base; 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-cell RNA sequencing; standard of care; therapeutic target; therapy resistant; transcriptome; transcriptome sequencing; 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）的特征是缺氧，营养缺乏， 缺乏免疫抑制的肿瘤微环境（TME）和可能损害治疗的纤维化基质 反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，肿瘤和基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相互作用将有助于深入了解PDAC进展， 治疗抵抗 特别地，癌症相关成纤维细胞（CAF）是TME的主要非免疫细胞组分，并且是TME的主要非免疫细胞组分。 由几种不同的亚型组成，这些亚型根据肿瘤亚型和周围环境而变化。 微环境生态位在这个提议中，我们汇集了一个多学科的团队， 研究人员将建立在我们以前的研究，以调查肿瘤TME共同组织者模型，重点是 询问PDAC肿瘤细胞和TME中CAF之间的相互作用。具体来说，我们将研究 肿瘤细胞和CAF之间的相互信号传导形成恶性细胞和CAF的总体假设 表型的上下文特异性的方式，可以通过先前的治疗和器官特异性的小生境调制。 我们将利用多种内置功能，包括基因工程小鼠模型（GEMM），患者- 衍生的类器官（PDO）和匹配的成纤维细胞模型，功能性遗传筛选和临床试验， 活组织检查以研究疾病进展和对治疗的抗性中的PDAC TME连续体。我们特别 建议（1）确定靶向器官特异性PDAC-CAF相互作用是否增强治疗效果 反应，（2）询问PDAC期间肿瘤细胞和CAF重编程引起的新漏洞 （3）研究TGFB阻断是否破坏肿瘤细胞-CAF串扰并使PDAC敏感， 化疗在进行这些研究时，我们将与PDAC基质重编程的其他成员合作， 联合会（PSRC）进行合作研究，以了解PDAC和TME的相互作用程序 肿瘤进展和治疗反应。