Senescent cancer-associated fibroblasts drive early-stage lymph node metastasis in pancreatic cancer through lactate-mediated metabolic-epigenetic rewiring
Menée à l'aide de lignées cellulaires, de xénogreffes sur des modèles murins et d'échantillons tumoraux issus de patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel les fibroblastes CAF sénescents favorisent le développement précoce de métastases ganglionnaires via l'augmentation du métabolisme du glucose et de la production de lactate
Lymph node metastasis (LNM) in early-stage PDAC predicts systemic dissemination and poor survival, yet its underlying mechanisms remain elusive. Here, we demonstrated that senescent cancer-associated fibroblasts (senCAFs) drive lymphatic remodeling and LNM in early-stage PDAC. Mechanistically, senCAFs increased glucose metabolism and lactate production, which activated lactylation-mediated serine metabolism to protect lymphatic endothelial cells from oxidative stress. Moreover, we discovered CCR4+ Tregs from the draining lymph nodes accumulated around lymphatic vessels, which established an immunosuppressive peri-lymphatic niche. High throughput drug screening determined selective clearance of senCAFs via chidamide, attenuated tumor progression and improved chemo-immunotherapeutic efficacy. We subsequently initiated a clinical trial (chidamide and nab-paclitaxel/gemcitabine plus anti-PD-1/CTLA-4) in metastatic PDAC patients and reported its preliminary promising results. Collectively, these findings reveal a closed link between cellular senescence and PDAC metastasis, offering the potential senolytic means to improve chemo-immunotherapy efficacy.
Cancer Discovery , résumé, 2026