Upregulated GDF-15 expression facilitates pancreatic ductal adenocarcinoma progression through orphan receptor GFRAL.

Zhiping Zhao,Jiali Yang,Junfeng Zhang,Huaizhi Wang,Bing Ni,Yao Zheng,Mengjie Zhang,Liangyu Yin

doi:10.18632/aging.103830

Abstract

Growth and differentiation factor 15 (GDF-15) has been studied as an important hallmark of cancer. However, the receptor of GDF-15 in pancreatic cancer cell remains unclear. Here, we investigated its biological effects in pancreatic ductal adenocarcinoma (PDAC). We found that aberrant GDF-15 expression positively correlated with poor survival of PDAC patients. GDF-15 protein enhanced tumor cell proliferation in two pancreatic cancer lines, AsPC-1 and BxPC-3. Knockdown GDF-15 attenuated its biological function in vitro and reduced PDAC cell tumorigenesis upon xenotransplantation into nude mice. Moreover, we identified that glial-derived neurotropic factor family receptor α-like (GFRAL) was upregulated in PDAC tissues and positively correlated with GDF-15 expression. High GFRAL expression was significantly associated with poor survival in PDAC patients. Furthermore, we identified that the biological effects of GDF-15 are mediated by its receptor GFRAL which is present in PDAC cells. After overexpression GFRAL in pancreatic cancer cells, the effect of GDF-15 was significantly enhanced. Overall, our findings demonstrated that the GDF-15 secreted by PDAC cells, binds to GFRAL, itself localized in PDAC cells, to promote cancer cell growth and metastasis through the GDF-15/GFRAL signaling pathway.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis largely owing to lethal malignancy, early metastasis, insignificant clinical symptoms and drug resistance [1, 2]
This study have demonstrated that the Growth and differentiation factor 15 (GDF-15) secreted by PDAC cells, binds to glial-derived neurotropic factor family receptor α-like (GFRAL), itself localized in PDAC cells, to promote cancer cell growth and metastasis
We found that PDAC cells can auto secrete GDF-15 protein, which was upregulated in pancreatic cancer tissues and blood samples compared with normal human pancreas and plasma

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis largely owing to lethal malignancy, early metastasis, insignificant clinical symptoms and drug resistance [1, 2]. The vast majority of patients with local progression and metastatic pancreatic cancer do not have opportunities to undergo a complete surgical resection. These patients have no other choice but to accept palliative resection [4, 5], chemotherapy [6, 7], radiotherapy [8], or immunological therapy [9]. These therapeutic methods have limited clinical benefits. It is urgent to find new early diagnostic and treatment options for PDAC

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Results

Conclusion