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

项目摘要/摘要 这项名为“致癌突触：细胞-细胞接触使巨噬细胞为基础的代谢”的项目 胰腺癌与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，以寻求对病因学意义的理解和进步 肿瘤细胞与肿瘤细胞间形成的突触样异型细胞接触的新功能 肿瘤相关成纤维细胞(CAF)。众所周知，CAF为癌细胞提供营养，并反过来- 诱导信号输入。胰腺癌，尤其是胰腺导管腺癌，是一种极端的疾病。 间质占优势的一例，其特殊的CAF特征可提供阴性预后。我们的 综合的和高度互补的初步发现是研究以前的 未知的异型细胞-细胞“致癌突触”结构及其PC支持功能。两个具体的 AIMS将验证PC细胞依赖NTNG1-NGL1参与形成致癌突触的假设 并通过Wnt5a调节的钙离子和磷脂酰丝氨酸(PtdSer)依赖的巨噬细胞来消耗胆固醇。 目标1将定义NTNG1-NGL1参与和功能性致癌突触的分子要求 队形。NTNG1和NGL1蛋白的分子工程和显微成像将定义结构 以及在CAF和PC细胞之间形成的致癌突触的功能细节。 目的2确定NTNG1/NGL1介导的致癌突触在巨噬细胞增多症中的重要性。基于 初步实验，我们将测试执行的PC细胞是否需要NTNG1-NGL1参与 巨噬细胞增多症。 促进巨噬细胞增多症的Caf-PC致癌突触所涉及的细胞-细胞接触结构尚未 已经被描述过了。因此，它们详细的分子和细胞生物学特性是至关重要的。这个 PC细胞对神经元突触机制的适应绕过了 PC微环境。因此，致癌突触可能是理解直接的CAF-PC细胞的关键。 支持恶性进展的细胞通讯。

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.