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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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Main Authors: Zhou, Xu (Author) , An, Jingyu (Author) , Kurilov, Roman (Author) , Brors, Benedikt (Author) , Hu, Kai (Author) , Peccerella, Teresa (Author) , Rössler, Stephanie (Author) , Pfütze, Katrin (Author) , Schulz, Angela (Author) , Wolf, Stephan (Author) , Hohmann, Nicolas (Author) , Theile, Dirk (Author) , Sauter, Max (Author) , Burhenne, Jürgen (Author) , Ei, Shigenori (Author) , Heger, Ulrike (Author) , Strobel, Oliver (Author) , Barry, Simon T. (Author) , Springfeld, Christoph (Author) , Tjaden, Christin (Author) , Bergmann, Frank (Author) , Büchler, Markus W. (Author) , Hackert, Thilo (Author) , Fortunato, Franco (Author) , Neoptolemos, John P. (Author) , Bailey, Peter (Author)
Format: Article (Journal)
Language:English
Published: 7 September 2023
In: Nature cancer
Year: 2023, Volume: 4, Issue: 9, Pages: 1362-1381
ISSN:2662-1347
DOI:10.1038/s43018-023-00628-6
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s43018-023-00628-6
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s43018-023-00628-6
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Author Notes:Xu Zhou, Jingyu An, Roma Kurilov, Benedikt Brors, Kai Hu, Teresa Peccerella, Stephanie 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 Büchler, Thilo Hackert, Franco Fortunato, John P. Neoptolemos, Peter Bailey
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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 GATA6hi and KRT17hi 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.
Item Description:Gesehen am 26.09.2023
Physical Description:Online Resource
ISSN:2662-1347
DOI:10.1038/s43018-023-00628-6

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