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

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.

Neoadjuvant chemo‐ or chemo‐radiation‐therapy of pancreatic ductal adenocarcinoma differentially shift ECM composition, complement activation, energy metabolism and ribosomal proteins of the residual tumor mass

“…In contrast with these findings, a RNA-Seq profiling study encompassed enriched ECM organization and collagen formation in NCT as compared to treatment-naïve PDAC. 38 A second gene expression study reported increased collagen transcription in NCRT-treated samples as compared to biopsies taken before the intended neoadjuvant therapy. 39 Taken together, this is an area of ongoing research, especially since a fibrotic ECM rich in collagens is a hallmark of PDAC, promoting tumor progression and chemoresistance.…”

Advances in the molecular regulation mechanism of tumor dormancy and its therapeutic strategy

“…This reversibility is a defining trait of tumor dormancy, underscoring its dynamic nature and the potential for dormant cells to re-enter active proliferation [ 25 ]. Drug-resistant persistent cells share some characteristics with dormant tumor cells in terms of reversibility; however, they differ in that removal from the drug environment promptly ends their dormancy, restoring sensitivity to the drug [ 34 ].…”

Diapause-like Drug-Tolerant Persister State: The Key to Nirvana Rebirth

“…Reversibility is also one of the important characteristics of the DTP state [18]. When a drug is discontinued, the tumor cells will regain sensitivity to the drug [19]. In other words, unlike the clonal evolution driven by gene mutations, the clonal complexity of recurrent tumors does not disappear during chemotherapy.…”