南方科技大学田瑞军与合作者，报道了胰腺癌细胞间信号的临床功能蛋白质组学。该研究于2024年11月13日发表于国际学术期刊《自然》杂志。

据了解，胰腺导管腺癌（PDAC）具有非典型、高体液的肿瘤微环境（TME），这是其不良预后的重要原因。

为了更好地了解PDAC中癌细胞与基质细胞之间的细胞间信号，研究人员开发了一种名为TMEPro的多维蛋白质组学方法。应用TMEPro对100份人胰腺组织样本的，糖基化分泌蛋白和质膜蛋白质组进行深入分析，研究确定了细胞类型起源，并发现了潜在的旁分泌交叉通讯，尤其是通过酪氨酸磷酸化介导的交叉信号。

研究人员在基因工程PDAC小鼠模型中，研究了胰腺肿瘤进展过程中的时间动态。在功能上，研究发现基质细胞和癌细胞之间，存在由基质PDGFR-PTPN11-FOS介导的互惠信号轴。

此外，研究人员还揭示了PDAC肿瘤中质膜蛋白脱落的一般机制，发现基质金属蛋白酶介导的AXL受体酪氨酸激酶细胞外结构域的脱落，为PDAC TME中细胞间信号调控提供了一个额外的维度。

重要的是，脱落的AXL水平与淋巴结转移有潜在的相关性，而且抑制AXL脱落及其激酶活性，在抑制癌细胞生长方面具有实质性的协同效应。

总之，TMEPro是一种通用的临床功能蛋白质组研究方法，提供了全面的资源可用于更好地了解PDAC TME，并促进发现新的诊断和治疗靶点。

附：英文原文

Title: Clinical functional proteomics of intercellular signalling in pancreatic cancer

Author: Huang, Peiwu, Gao, Weina, Fu, Changying, Wang, Min, Li, Yunguang, Chu, Bizhu, He, An, Li, Yuan, Deng, Xiaomei, Zhang, Yehan, Kong, Qian, Yuan, Jingxiong, Wang, Hebin, Shi, Yu, Gao, Dong, Qin, Renyi, Hunter, Tony, Tian, Ruijun

Issue&Volume: 2024-11-13

Abstract: Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis1. Here, to better understand the intercellular signalling between cancer and stromal cells directly in PDAC tumours, we developed a multidimensional proteomic strategy called TMEPro. We applied TMEPro to profile the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples to a great depth, define cell type origins and identify potential paracrine cross-talk, especially that mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumour progression were investigated in a genetically engineered PDAC mouse model. Functionally, we revealed reciprocal signalling between stromal cells and cancer cells mediated by the stromal PDGFR–PTPN11–FOS signalling axis. Furthermore, we examined the generic shedding mechanism of plasma membrane proteins in PDAC tumours and revealed that matrix-metalloprotease-mediated shedding of the AXL receptor tyrosine kinase ectodomain provides an additional dimension of intercellular signalling regulation in the PDAC TME. Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets.

DOI: 10.1038/s41586-024-08225-y

Source: https://www.nature.com/articles/s41586-024-08225-y