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.

项目摘要/摘要 该项目的标题为“致癌突触：细胞电池触点，可实现基于trogocytic的代谢 胰腺癌与成纤维细胞基质细胞之间的相互作用直接解决NCI 挑衅性问题（PQ）＃7在寻求理解病理学意义的进步方面 癌细胞和 癌症相关的成纤维细胞（CAF）。众所周知，CAF为癌细胞提供养分和相互的营养 诱导信号输入。胰腺癌（PC），尤其是胰腺导管腺癌，是一个极端 基质的优势示例，其中特定的CAF特征会涉及负预后。我们的 结合和高度互补的初步发现是研究以前的 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 目标将检验以下假设：PC细胞依赖NTNG1-NGL1参与以形成致癌突触 并通过WNT5A调节的Ca2+和磷脂酰丝氨酸（PTDSER）依赖性的trogocyocycocycocypososis消耗胆固醇。 AIM 1将定义NTNG1-NGL1参与和功能性致癌突触的分子要求 形成。 NTNG1和NGL1蛋白和显微镜成像的分子工程将定义结构 CAF和PC细胞之间形成的致癌突触的功能细节。 AIM 2将确定NTNG1/NGL1介导的肌细胞增多症的致癌突触的重要性。基于 初步实验，我们将测试是否需要PC细胞执行的NTNG1-NGL1参与度 trog细细胞增多症。 CAF-PC致癌突触中涉及的细胞电池接触结构促进trogococytosis尚未 先前描述了。因此，它们详细的分子和细胞生物学表征至关重要。这 PC细胞对神经元突触机制的适应绕过了由 PC微环境。这是，致癌突触可能是了解直接CAF-PC细胞的关键 细胞通信认可恶性进展。