Key Takeaways & Executive Findings
- •• Pancreatic stellate cells (PSCs) promote ferroptosis resistance in pancreatic cancer cells through a paracrine mechanism. • IL15 secreted by PSCs activates the IL15RA-STAT3-GPX4/ACSL3 signaling axis, upregulating both GPX4 and ACSL3 to prevent lipid peroxidation. • The IL15RA-STAT3-GPX4/ACSL3 axis protects pancreatic cancer cells from ferroptosis both in vitro and in vivo, suggesting a novel therapeutic target. • Targeting this signaling pathway may overcome ferroptosis resistance and improve treatment outcomes in pancreatic ductal adenocarcinoma (PDAC).
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a poor prognosis, and the lack of effective treatment methods accounts for its high mortality. Pancreatic stellate cells (PSCs) in the tumor microenvironment play an important role in the development of PDAC. Previous studies have reported that patients with PDAC are more vulnerable to ferroptosis inducers. To investigate the relationship between PSCs and pancreatic cancer cells, a coculture system is used to further reveal the influence of PSCs on ferroptosis resistance in PDAC using many in vitro and in vivo experiments. Our results show that PSCs promote ferroptosis resistance in pancreatic cancer cells. We further demonstrate that IL15 secretion by PSCs activates the IL15RA-STAT3-GPX4/ACSL3 axis. The simultaneous upregulation of GPX4 and ACSL3 prevents lipid peroxidation and ultimately protects pancreatic cancer cells from ferroptosis both in vitro and in vivo. This study demonstrates that PSCs protect pancreatic cancer cells in a paracrine manner and may indicate a novel strategy for the treatment of PDAC.
1. Introduction
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a poor prognosis, and the lack of effective treatment methods accounts for its high mortality. Pancreatic stellate cells (PSCs) in the tumor microenvironment play an important role in the development of PDAC. Patients with PDAC urgently need effective treatment because the prognosis is very poor, and the 5-year survival rate is only 10% [1].
Ferroptosis is a unique form of cell death resulted from the overwhelming iron-dependent accumulation of lethal amounts of ROS [2]. Although ferroptosis is a promising strategy in various drug-resistant tumors, cancer cells have developed multiple resistance mechanisms to protect themselves from ferroptosis. Ferroptosis has been widely studied in ovarian cancer, breast cancer, liver cancer, rectal cancer and lung cancer. However, few studies have investigated ferroptosis in pancreatic cancer. Recently, the role of ferroptosis in pancreatic cancer has attracted the attention of researchers. Inducing ferroptosis in pancreatic cancer cells may inhibit tumor growth and reduce tumor chemoresistance.
PDAC has a dismal prognosis, perhaps partially because severe desmoplastic reaction may prevent classic chemotherapeutic drugs from accessing tumor cells [3]. PSCs are the main cells that cause desmoplastic reactions in patients with PDAC [4,5]. However, the relationship between parenchymal cells and stromal cells is far greater [6,7]. To date, several types of cell death, including apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis, have been described [2]. Recently, several reports revealed that PDAC is more vulnerable to ferroptosis inducers [8]. However, the underlying mechanisms of ferroptosis resistance in pancreatic cancer mediated by stromal cells in the tumor microenvironment remain unknown.
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Di Wu, Zhiliang Wang, Yue Zhang, Yang Yang, Yue Yang, Guangchen Zu, Xianjun Yu, Weibo Chen, Yi Qin, Xiaowu Xu, Xuemin Chen (2026). IL15RA-STAT3-GPX4/ACSL3 signaling leads to ferroptosis resistance in pancreatic cancer. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024153
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Frequently Asked Questions
What is the role of pancreatic stellate cells (PSCs) in pancreatic cancer ferroptosis resistance?
PSCs secrete IL15, which activates the IL15RA-STAT3-GPX4/ACSL3 axis in pancreatic cancer cells, upregulating GPX4 and ACSL3 to prevent lipid peroxidation and thereby conferring ferroptosis resistance.
How does IL15 signaling protect pancreatic cancer cells from ferroptosis?
IL15 binds to IL15RA on pancreatic cancer cells, activating STAT3, which transcriptionally upregulates GPX4 and ACSL3. These proteins work together to reduce lipid peroxidation, protecting cells from ferroptosis.
What is the significance of the IL15RA-STAT3-GPX4/ACSL3 axis in PDAC treatment?
This axis represents a potential therapeutic target. Inhibiting this pathway could sensitize pancreatic cancer cells to ferroptosis inducers, offering a novel strategy to overcome drug resistance and improve patient outcomes.
What experimental models were used in this study?
The study utilized a coculture system of pancreatic stellate cells and pancreatic cancer cell lines (PANC-1 and SW1990), along with in vivo experiments, to investigate the effects of PSCs on ferroptosis resistance.
What are the key molecules involved in the ferroptosis resistance mechanism?
Key molecules include IL15 (secreted by PSCs), IL15RA (receptor on cancer cells), STAT3 (transcription factor), and GPX4 and ACSL3 (effector proteins that prevent lipid peroxidation).
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