Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC
Xu Zhou, Jingyu An, Roma Kurilov, Benedikt Brors, Kai Hu, Teresa Peccerella, Stéphanie Roessler, Katrin Pfütze, Angela Schulz, Stephan Wolf, Nicolas Hohmann, Dirk Theile, Max Sauter, Jürgen Burhenne, Shigenori Ei, Ulrike Heger, Oliver Strobel, Simon T. Barry, Christoph Springfeld, Christine Tjaden, Frank Bergmann, Markus W. Büchler, Thilo Hackert, Franco Fortunato, John P. Neoptolemos, Peter J. Bailey
Abstract
Abstract Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing ( n = 97) and multiplexed immunofluorescence ( n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6 hi and KRT17 hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.