Chemotherapy-Induced Oral Mucosal Injury Is Defined by p53 Activation, Cell Cycle Arrest and Diverse Epithelial Progenitor Dynamics
Silva, P. H. F.; Li, L.; Muriel, M.; Brennan, T.; Hasanuzzaman, M.; Demoura, M.; Stampfer, J.; Sveinsson, M.; Fountzilas, C.; Schabert, J. E.; Singh, A. K.; Bard, J. E.; Schlecht, N. F.; Ikonomou, L.; Diaz, P. I.
Show abstract
Chemotherapy-induced oral mucositis is a common and debilitating complication, yet the mechanisms underlying oral mucosa injury and repair remain poorly defined. Using a mouse model of 5-fluorouracil (5-FU)-induced mucositis, we define gene networks and oral mucosal cellular landscape dynamics in response to chemotoxic stress. We show that 5-FU-induced epithelial atrophy is driven primarily by cell cycle arrest rather than apoptosis, despite concurrent activation of p53-dependent transcriptional programs linked to both cell fates within individual cells. Relative to intestine, the recovering oral mucosa exhibits a more effective cell cycle checkpoint response and uniquely undergoes metabolic reprogramming toward lipid oxidation. Single-cell RNA sequencing revealed putative epithelial progenitor populations with distinct responses to chemotherapy, including chemoresistant cells with a p53- and AP-1 complex gene signature, reminiscent of lung transitional cell states. These findings define diverse progenitor dynamics and p53-driven responses as key determinants of oral mucosal injury and repair following chemotherapy.
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