Oncogenic Synapses: cell-cell contacts enabling trogocytic-based metabolic interactions between pancreatic cancer and fibroblastic stromal cells

致癌突触：细胞与细胞的接触使胰腺癌和成纤维基质细胞之间基于 Trogocytic 的代谢相互作用成为可能

• 批准号: 9894770
• 负责人: Igor Astsaturov
• 金额: $ 20.05万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894770
• 关键词: Ablation; Address; Area; Binding; Biology; Bypass; Cell Communication; Cell membrane; Cells; Cellular Structures; Cellular biology; Characteristics; Cholesterol; Cholesterol Homeostasis; Communication; Consumption; Data; Dependence; Development; Electron Microscopy; Elements; Engineering; Epithelial Cells; Extracellular Matrix; Fibroblasts; Genes; Genetic; Imaging Device; Immunosuppression; Interphase; Investigation; Knock-out; Label; Lesion; Ligands; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Membrane; Membrane Lipids; Metabolic; Molecular; Molecular Biology; Neurons; Nutrient; Nutritional; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic carcinoma; Pathway interactions; Pharmacology; Phosphatidylserines; Pilot Projects; Play; Prevention; Process; Proteins; Proteomics; Recombinant Proteins; Resistance; Role; SHH gene; Signal Transduction; Sterols; Stromal Cells; Structure; Suggestion; Synapses; Synaptosomes; Testing; Up-Regulation; Work; base; cancer cell; conditional knockout; experimental study; innovation; microscopic imaging; mutant; neoplastic; netrin-G1; novel; outcome forecast; pancreatic cancer cells; paracrine; quantitative imaging; receptor; stellate cell; synaptogenesis; tool; tumor; tumor growth; tumor microenvironment; tumorigenesis

PROJECT SUMMARY/ABSTRACT The project titled “Oncogenic Synapses: cell-cell contacts enabling trogocytic-based metabolic interactions between pancreatic cancer and fibroblastic stromal cells” directly addresses the NCI Provocative Question (PQ) #7 in seeking advancement in understanding of the pathognomonic significance and functions of newly described synapse-like heterotypic cell-cell contacts formed between carcinoma cells and cancer-associated fibroblasts (CAFs). CAFs are known to provide cancer cells with nutrients and reciprocally- induced signaling inputs. Pancreatic cancer (PC), particularly pancreatic ductal adenocarcinoma, is an extreme example of preponderance of stroma in which particular CAF characteristics confer negative prognosis. Our combined and highly complementary preliminary findings serve as a basis to study the previously uncharacterized heterotypic cell-cell “oncogenic synapse” structure and its PC supportive function. Two specific aims will test the hypothesis that PC cells depend on NTNG1-NGL1 engagement to form oncogenic synapses and consume cholesterol via Wnt5a-regulated Ca2+ and phosphatidylserine (PtdSer)-dependent trogocytosis. Aim 1 will define the molecular requirements for NTNG1-NGL1 engagement and functional oncogenic synapse formation. Molecular engineering of NTNG1 and NGL1 proteins and microscopy imaging will define the structural and functional particulars of the oncogenic synapses formed between CAF and PC cells. Aim 2 will determine the importance of NTNG1/NGL1-mediated oncogenic synapses in trogocytosis. Based on preliminary experiments, we will test if NTNG1-NGL1 engagement is needed for the PC cell-executed trogocytosis. The cell-cell contact structures involved in the CAF-PC oncogenic synapses that facilitate trogocytosis have not been previously described. Therefore, their detailed molecular and cell biology characterization is critical. The adaptation of neuronal synapse mechanisms by PC cells bypasses the metabolic restrictions imposed by the PC microenvironment. Thus, the oncogenic synapses may be the key to understanding the direct CAF-PC cell- cell communication which endorses malignant progression.

项目概要/摘要 该项目名为“致癌突触：细胞与细胞的接触使基于 Trogocytic 的代谢成为可能” 胰腺癌和成纤维细胞基质细胞之间的相互作用”直接解决了 NCI 挑衅性问题 (PQ) #7 寻求对病理意义和理解的进步 新描述的癌细胞和细胞之间形成的突触样异型细胞接触的功能 众所周知，癌症相关成纤维细胞（CAF）可以为癌细胞提供营养，并相互提供营养。 胰腺癌（PC），特别是胰腺导管腺癌，是一种极端的癌症。 基质占优势的例子，其中特定的 CAF 特征导致阴性预后。 综合且高度互补的初步研究结果可作为研究先前研究的基础 未表征的异型细胞-细胞“致癌突触”结构及其 PC 支持功能。 目标将检验 PC 细胞依赖 NTNG1-NGL1 结合形成致癌突触的假设 并通过 Wnt5a 调节的 Ca2+ 和磷脂酰丝氨酸 (PtdSer) 依赖性的吞噬作用消耗胆固醇。 目标 1 将定义 NTNG1-NGL1 接合和功能性致癌突触的分子要求 NTNG1 和 NGL1 蛋白的分子工程和显微镜成像将定义其结构。 以及 CAF 和 PC 细胞之间形成的致癌突触的功能细节。 目标 2 将确定 NTNG1/NGL1 介导的致癌突触在 trogocytosis 中的重要性。 初步实验，我们将测试 PC 细胞执行是否需要 NTNG1-NGL1 接合 胞吞作用。 参与 CAF-PC 致癌突触的细胞-细胞接触结构促进了吞噬作用，但尚未发现 因此，它们的详细分子和细胞生物学特征至关重要。 PC细胞对神经突触机制的适应绕过了由PC细胞施加的代谢限制 因此，致癌突触可能是了解直接 CAF-PC 细胞的关键。 支持恶性进展的细胞通讯。