Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.
Liu Xinxin, Huang Zhihua, Yang Bohan, Du Yimeng, Sun Yixin, Zhang Enkui, Kang Xiaofeng, Xue Chunyuan, Chen Kai, Ma Yongsu, Tian Xiaodong, Xu Xiaojie, Yang Yinmo
Abstract
Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) is partly driven by pathological stromal remodeling, yet the underlying mechanisms remain poorly understood. Here, we show that gemcitabine treatment induces tumor cell senescence and activates cancer-associated fibroblasts via the senescence-associated secretory phenotype, leading to progressive fibrotic matrix stiffening. This biomechanical reprogramming engages the mechanosensitive ion channel Piezo1, triggering metabolic rewiring that renders BRG1-positive tumor cells increasingly dependent on NRF2-mediated antioxidant defenses. Piezo1 signaling promotes NRF2 nuclear translocation and its chromatin-remodeling cooperation with BRG1, thereby upregulating SLC7A11-dependent antioxidant programs and suppressing ferroptosis. Notably, the combination of the senolytic agent ABT-263 with the ferroptosis inducer Erastin effectively dismantles BRG1-NRF2-driven gemcitabine resistance, alleviates stromal fibrosis, enhances T-cell infiltration, and suppresses tumor growth in vivo. This senolytic-ferroptosis approach exploits metabolic vulnerabilities in chemotherapy-aged PDAC and provides a mechanistic rationale for stroma-targeted combination therapies.
Key Findings
- Gemcitabine treatment induces tumor cell senescence and activates cancer-associated fibroblasts, leading to stromal matrix stiffening in PDAC.
- Stromal stiffening activates Piezo1, which promotes NRF2 nuclear translocation and cooperation with BRG1, upregulating antioxidant defenses and suppressing ferroptosis.
- Combining senolytic agent ABT-263 with ferroptosis inducer Erastin overcomes gemcitabine resistance, reduces fibrosis, enhances T-cell infiltration, and suppresses tumor growth.
Clinical Significance
The study identifies a novel therapeutic strategy targeting NRF2-mediated antioxidant adaptation and stromal remodeling to overcome chemoresistance in pancreatic cancer, supporting the use of senolytic and ferroptosis-inducing agents in combination therapies.
Citation
Liu Xinxin, Huang Zhihua, Yang Bohanet al.. Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma. Nature communications. 2026-Jul-18.