Human splenic TER cells: A relevant prognostic factor acting via the artemin‐GFRα3‐ERK pathway in pancreatic ductal adenocarcinoma

• Published in: International journal of cancer Vol. 148; no. 7; pp. 1756 - 1767
• Main Authors: Li, Tian‐Jiao, Li, Hao, Zhang, Wu‐Hu, Xu, Shuai‐Shuai, Jiang, Wang, Li, Shuo, Gao, He‐Li, Han, Xuan, Xu, Hua‐Xiang, Wu, Chun‐Tao, Wang, Wen‐Quan, Yu, Xian‐Jun, Liu, Liang
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.04.2021; Wiley Subscription Services, Inc
• Subjects: Adenocarcinoma; artemin; Cancer; Cell proliferation; Extracellular signal-regulated kinase; Flow cytometry; Immunofluorescence; Lymph nodes; Medical research; Metabolic pathways; Metastases; Pancreas; Pancreatic cancer; Patients; PDAC; Prognosis; Signal transduction; Spleen; Splenectomy; Surgery; TER cell; Tumors; PDAC; prognosis; TER cell; splenectomy; artemin
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.33410

Splenectomy is routinely performed during distal or total pancreatectomy (DP or TP) for pancreatic ductal adenocarcinoma (PDAC), but information about its oncological value is limited. TER cells, nonimmune cells discovered in the spleens of tumour‐bearing mice, are elicited by tumours and promote tumour progression, while their role in the clinical outcomes of patients with PDAC remains unclear. In our study, postoperative specimens from 622 patients who underwent DP or TP with splenectomy were analysed by flow cytometry or immunofluorescence, and the relationship between splenic TER cell count and clinical parameters was calculated. We also purified human TER cells for functional experiments and mechanistic studies. We found that TER cell numbers were increased only in the spleens of patients with PDAC but not in PDAC tissue and adjacent pancreatic tissue. High splenic TER cell counts independently predicted poor prognosis (P < .001) and indicated large tumour size, lymph node metastasis, advanced 8th AJCC/mAJCC stage and high CA19‐9 classification (all P < .050) in patients with PDAC. Mechanistic analysis showed that TER cells express artemin, which facilitates the proliferation and invasion of PDAC cells by activating GFRα3‐ERK signalling. Our study reveals that TER cell count is an indicator of poor prognosis of PDAC, while splenectomy during pancreatic surgery might provide oncological benefits in addition to ensuring the radical resection of PDAC. What's new? Splenic TER cells, nonimmune cells enriched during tumor progression, are suspected of promoting cancer cell survival and metastasis through remote signaling pathways. Little is known, however, about how TER cells impact tumor progression or whether they are clinically relevant. In this investigation of pancreatic ductal adenocarcinoma (PDAC) patients, TER cell number was found to be significantly increased in the spleen, with higher TER cell number predicting poor surgical outcome. Human TER cells secreted the neurotropic factor artemin and promoted PDAC cell malignancy via GFRα3‐ERK signaling activation. The findings suggest that splenectomy may be beneficial in the surgical treatment of PDAC.