Journal Article

DKFZ-2023-01832

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC.

Zhou, X. ; An, J. ; Kurilov, R. (First author)DKFZ* ; Brors, B.DKFZ* ; Hu, K. ; Peccerella, T. ; Roessler, S. ; Pfütze, K.DKFZ* ; Schulz, A.DKFZ* ; Wolf, S.DKFZ* ; 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. ; Bailey, P.

2023
Nature Research London

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Please use a persistent id in citations: doi:10.1038/s43018-023-00628-6

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.

Note: #EA:B330# / 2023 Sep;4(9):1362-1381

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Contributing Institute(s):

1. Angewandte Bioinformatik (B330)
2. DKTK HD zentral (HD01)
3. Translationale Medizinische Onkologie (B340)
4. Hochdurchsatz-Sequenzierung (W190)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Nature ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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