Arl4c promotes the growth and drug resistance of pancreatic cancer by regulating tumor-stromal interactions

Xin Chen,Yanzhen Zhang,Weikun Qian,Liang Han,Wei Li,Wanxing Duan,Zheng Wu,Zheng Wang,Qingyong Ma

doi:10.1016/j.isci.2021.103400

Xin Chen, Yanzhen Zhang + Show 7 more

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https://doi.org/10.1016/j.isci.2021.103400

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Abstract

SummaryEmerging evidence suggests that ADP-ribosylation factor like-4c (Arl4c) may be a potential choice for cancer treatment. However, its role in pancreatic cancer, especially in tumor-stroma interactions and drug resistance, is still unknown. In the current study, we examined the proliferation and drug resistance effect of Arl4c on pancreatic cancer cells. Furthermore, we explored the contribution of Arl4c high expression in pancreatic stellate cell (PSC) activation. We found that high Arl4c expression is associated with cell proliferation, drug resistance, and PSC activation. In detail, Arl4c regulates connective tissue growth factor (CTGF) paracrine, further induces autophagic flux in PSCs, resulting in PSC activation. TGFβ1 secreted by activated PSCs enhances cancer cell stem cell properties via smad2 signaling, further increasing cell drug resistance. YAP is an important mediator of the Arl4c-CTGF loop. Taken together, these results suggest that Arl4c is essential for pancreatic cancer progression and may be an effective therapeutic choice.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world, with a 5-year survival rate of less than 9% (Siegel et al, 2020)
Pancreatic cancer is characterized by a severe desmoplastic reaction that consists of activated pancreatic stellate cells (PSCs), lymphocytes, macrophages, vascular endothelial cells, extracellular matrix (ECM) and other components, creating a complex tumor microenvironment that promotes tumor growth, metastasis, and drug resistance (Dougan, 2017)
We aimed to explore the role of ADP-ribosylation factor like-4c (Arl4c) in pancreatic cancer growth and drug resistance, as well as PSC activation, further determine its effect on tumor-stromal interactions, and reveal the underlying mechanism

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world, with a 5-year survival rate of less than 9% (Siegel et al, 2020). With the improvement of medical instruments, an increasing number of patients are diagnosed with pancreatic cancer at an early tumor stage. At present, only approximately 10% of patients are diagnosed with standard surgically resectable pancreatic cancer (Strobel et al, 2019). Local invasion and drug resistance remain two obstacles resulting in a poor cancer prognosis. Pancreatic cancer is characterized by a severe desmoplastic reaction that consists of activated pancreatic stellate cells (PSCs), lymphocytes, macrophages, vascular endothelial cells, extracellular matrix (ECM) and other components, creating a complex tumor microenvironment that promotes tumor growth, metastasis, and drug resistance (Dougan, 2017).

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