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.

项目总结/摘要 该项目名为“致癌突触：细胞与细胞接触， 胰腺癌和成纤维基质细胞之间的相互作用”直接解决了NCI 挑衅性问题（PQ）#7，以寻求进一步理解病理学意义， 新描述的在癌细胞之间形成的突触样异型细胞-细胞接触的功能， 癌相关成纤维细胞（CAF）。已知CAF为癌细胞提供营养和维生素， 诱导信号输入。胰腺癌（PC），特别是胰腺导管腺癌，是一种极端的癌症。 间质优势的例子，其中特定的CAF特征赋予阴性预后。我们 综合和高度互补的初步调查结果作为研究以前的基础， 未表征的异型细胞-细胞“致癌突触”结构及其PC支持功能。两个具体 目的是检验PC细胞依赖于NTNG 1-NGL 1接合形成致癌突触的假设 并通过Wnt 5a调节的Ca 2+和磷脂酰丝氨酸（PtdSer）依赖性胞饮作用消耗胆固醇。 目的1将明确NTNG 1-NGL 1结合和功能性致癌突触的分子要求 阵NTNG 1和NGL 1蛋白的分子工程和显微成像将确定结构 以及CAF和PC细胞之间形成的致癌突触的功能细节。 目的2将确定NTNG 1/NGL 1介导的致癌突触在胞啃中的重要性。基于 在初步实验中，我们将测试NTNG 1-NGL 1接合是否需要PC细胞执行 胞啃 参与CAF-PC致癌突触的细胞-细胞接触结构促进了胞吞作用， 以前描述过。因此，其详细的分子和细胞生物学表征至关重要。的 PC细胞对神经元突触机制的适应绕过了 PC微环境。因此，致癌性突触可能是理解CAF-PC细胞直接作用的关键。 支持恶性进展的细胞通讯。