GREM1 is a novel serum diagnostic marker and potential therapeutic target for pancreatic ductal adenocarcinoma

Sen Yang; Yalu Zhang; Yuze Hua; Ming Cui; Mengyi Wang; Junyi Gao; Qiaofei Liu; Quan Liao

doi:10.3389/fonc.2022.968610

GREM1 is a novel serum diagnostic marker and potential therapeutic target for pancreatic ductal adenocarcinoma

Front Oncol. 2022 Aug 26:12:968610. doi: 10.3389/fonc.2022.968610. eCollection 2022.

Authors

Sen Yang¹, Yalu Zhang^{1

2}, Yuze Hua¹, Ming Cui¹, Mengyi Wang¹, Junyi Gao¹, Qiaofei Liu¹, Quan Liao¹

Affiliations

¹ Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
² Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.

Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm with rising incidence worldwide. Gremlin 1 (GREM1), a regulator of bone morphogenetic protein (BMP) signaling, fine-tunes extensive biological processes, including organ morphology, cellular metabolism, and multiple pathological developments. The roles of GREM1 in PDAC remain unknown.

Methods: Varieties of public databases and online software were employed to analyze the expressions at transcription and protein levels of GREM1 in multiple malignant neoplasms including PDAC, and in addition, its potential pro-tumoral functions in PDAC were further evaluated. A total of 340 serum samples of pancreatic disease, including PDAC, low-grade malignant pancreatic neoplasm, benign pancreatic neoplasm, pancreatitis, and 132 healthy controls, were collected to detect GREM1. The roles of serum GREM1 in the diagnosis and prediction of survival of PDAC after radical resection were also analyzed.

Results: Bioinformatics analyses revealed that GREM1 was overexpressed in PDAC and predicted a poorer survival in PDAC. A higher protein level of GREM1 in PDAC correlated with stroma formation and immunosuppression by recruiting varieties of immunosuppressive cells, including T regulatory cells (Tregs), M2 macrophages, myeloid-derived suppressor cells (MDSCs), and exhaustion T cells into the tumor microenvironment. A higher level of serum GREM1 was observed in PDAC patients, compared to healthy control (p < 0.001). Serum GREM1 had a good diagnostic value (area under the curve (AUC) = 0.718, p < 0.001), and its combination with carbohydrate antigen 199 (CA199) achieved a better diagnostic efficacy (AUC = 0.914, p < 0.001), compared to CA199 alone. The cutoff value was calculated by receiver operating characteristic (ROC) analysis, and PDAC patients were divided into two groups of low and high GREM1. Logistic analyses showed serum GREM1 positively correlated with tumor size (hazard ratio (HR) = 7.097, p = 0.032) and histopathological grades (HR = 2.898, p = 0.014). High-level serum GREM1 (1,117.8 pg/ml) showed a shorter postoperative survival (p = 0.0394).

Conclusion: Higher intra-tumoral expression of GREM1 in PDAC contributes to tumor stroma and immunosuppressive tumor microenvironment, presenting its therapeutic potential. High-level serum GREM1 predicts poorer survival after resection. A combination of serum CA199 and GREM1 shows a stronger diagnostic efficacy in PDAC.

Keywords: diagnosis; gremlin 1 (GREM1); marker; pancreatic adenocarcinoma (PDAC); tumor microenvironment.