Chemotherapy-induced fibroblast switch fuels pancreatic cancer resistance
- Single-cell profiling of pancreatic tumors showed that albumin-bound paclitaxel plus gemcitabine shifts cancer-associated fibroblasts from myofibroblastic to inflammatory states and expands a TMEM100+ subset in nonresponders.
- Paclitaxel engages IL-2–STAT5 signaling to induce TMEM100; these fibroblasts secrete amphiregulin, which activates EGFR on tumor cells and promotes resistance.
- Genetic removal of TMEM100+ fibroblasts in mice reversed the switch and improved chemotherapy response, nominating them as a target.
💡 Points Based on the abstract
Ablating TMEM100+ fibroblasts in mice shows necessity, not druggability, and TMEM100 itself looks like a poor handle. The tractable node is AREG-EGFR, where EGFR inhibitors already exist, though erlotinib's modest benefit in pancreatic cancer tempers expectations. The decisive experiment is paired pre/post-treatment biopsies plus nab-paclitaxel combined with EGFR or ADAM17 blockade, tracking CAF plasticity.
📄 Paper · Science Translational Medicine ↗ Albumin-bound paclitaxel–induced stromal reprogramming drives resistance to neoadjuvant chemotherapy in patients with pancreatic cancer