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

Zhou, X. et al. (2023) Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC. Nature Cancer, 4, pp. 1362-1381. (doi: 10.1038/s43018-023-00628-6) (PMID:37679568) (PMCID:PMC10518256)

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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 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 Type:Articles
Additional Information:The EPZ is supported by the Heidelberger Stiftung Chirurgie (M.B.) and the German Ministry for Education and Research (Bundesministerium für Bildung und Forschung) grants 01GS08114 and 01ZX1305C (T.H. and M.B.). This research was also supported by Heidelberger Stiftung Chirurgie (F.F. and J.P.N.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bailey, Dr Peter
Authors: Zhou, X., An, J., Kurilov, R., Brors, B., Hu, K., Peccerella, T., Roessler, S., Pfütze, K., Schulz, A., Wolf, S., Hohmann, N., Theile, D., Sauter, M., Burhenne, J., Ei, S., Heger, U., Strobel, O., Barry, S. T., Springfeld, C., Tjaden, C., Bergmann, F., Büchler, M., Hackert, T., Fortunato, F., Neoptolemos, J. P., and Bailey, P.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Cancer
Publisher:Nature Research
ISSN:2662-1347
ISSN (Online):2662-1347
Published Online:07 September 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Nature Cancer 4:1362–1381
Publisher Policy:Reproduced under a Creative Commons License

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