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Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC

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...

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Published in:Nature cancer 2023-09, Vol.4 (9), p.1362-1381
Main Authors: Zhou, Xu, An, Jingyu, Kurilov, Roma, Brors, Benedikt, Hu, Kai, Peccerella, Teresa, Roessler, Stephanie, Pfütze, Katrin, Schulz, Angela, Wolf, Stephan, Hohmann, Nicolas, Theile, Dirk, Sauter, Max, Burhenne, Jürgen, Ei, Shigenori, Heger, Ulrike, Strobel, Oliver, Barry, Simon T, Springfeld, Christoph, Tjaden, Christine, Bergmann, Frank, Büchler, Markus, Hackert, Thilo, Fortunato, Franco, Neoptolemos, John P, Bailey, Peter
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Language:English
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Summary: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 and KRT17 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.
ISSN:2662-1347
2662-1347
DOI:10.1038/s43018-023-00628-6