Deciphering transcriptional plasticity in pancreatic ductal adenocarcinoma reveals alterations in sensory neuron innervation

Sep 22, 2026

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Neuronal innervation of the pancreas has been incompletely mapped at the transcriptomic level, limiting understanding of how neural remodeling affects pancreatic ductal adenocarcinoma (PDAC) progression and pain signaling. This study uses Fast Blue retrotracing in wild-type and PDAC mouse models, followed by single-cell RNA sequencing of sensory neurons from the pancreatic head and tail, validated by immunofluorescence, organoid cultures, and qPCR. Neurofilament-containing neurons dominate in both contexts, while non-peptidergic neurons are reduced in tumor-associated innervation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Neural circuits in pancreas homeostasis

Neural remodeling in cancer and PDAC

Methods

Fast Blue retrotracing and sensory neuron isolation

Single-cell RNA sequencing and validation

Results

Sensory neuron subtype shifts under normal vs PDAC conditions

Tumor-specific mitochondrial gene upregulation

Extracellular vesicle–mediated transcript transfer

Deciphering transcriptional plasticity in pancreatic ductaladenocarcinoma reveals alterations in sensory neuron innervation Elena Genova 1 , Michele Montrone2, Uday Rangaswamy2, Francesco Diversi2, Irene Schiavo2, Denise Ferrarini2, Roberta Di Florio2 , Irene Longo2, Michele Coscia2, Nicola Zamboni2, Giorgia Demontis2, Lisa Veghini3, Vincenzo Corbo3, Remo Sanges2 and Paul Heppenstall2 1 Institute for Maternal and Child Health- IRCCS “Burlo Garofolo”, Trieste, Italy 2 Scuola Internazionale Superiore di Studi Avanzati, Trieste, Italy 3 Department of Engineering for Innovation Medicine, University of Verona, Italy Keywords pancreas; pancreatic ductaladenocarcinoma; sensory neurons; singlecell RNA sequencing; tumor microenvironment Correspondence P. Heppenstall, Scuola Internazionale Superiore di Studi Avanzati, 34136, Trieste, Italy E-mail: [pheppens@sissa.it](pheppens@sissa.it)[ ](pheppens@sissa.it)and E. Genova, IRCCS Burlo Garofolo, 34137, Trieste, Italy E-mail: [elena.genova@burlo.trieste.it](elena.genova@burlo.trieste.it) Elena Genova, Michele Montrone, and Uday Rangaswamy contributed equally to this work. (Received 4 November 2025, revised 22 January 2026, accepted 20 February 2026, available online 18 March 2026) doi:10 . 1002/1878-0261 .70233 Neuronal innervation of the pancreas has historically been characterized using marker-based classiﬁcation and physiological studies, but its transcriptomic landscape remains only partially explored. A detailed molecular proﬁle of pancreatic sensory neurons could provide insights into their role in health and disease, particularly in pancreatic ductal adenocarcinoma (PDAC), where neural remodeling inﬂuences tumor progression and pain signaling. Wild-type and PDAC mice were injected with the retrotracer Fast Blue into pancreatic or cancerous tissue. Dorsal root ganglia were dissociated, and Fast Blue-positive sensory neurons were isolated, lysed, and analyzed using single-cell RNA sequencing. Data were validated using immunoﬂuorescence, organoid cultures and qPCR. We performed transcriptomic proﬁling of sensory neurons innervating the pancreatic head and tail under normal and cancer conditions. Our analysis identiﬁed neuroﬁlament-containing neurons asthe predominant sensory subtype in both contexts, while non-peptidergic neurons were underrepresented in tumor-associated innervation. Differential gene expression analysis revealed a unique subset of genes upregulated in sensory neurons innervating pancreatic tumors, many linked to mitochondrial activity. Further validation also revealed the presence of transcripts transferred via extracellular vesicles (including the Pdx1-CreERT2 transgene from the KPC mouse model), suggesting a novel mechanism of tumor– neuron interaction. Our ﬁndings provide a detailed characterization of pancreatic and pancreatic ductal adenocarcinoma sensory innervation. We identiﬁed tumor-derived RNA within sensory neurons in the PDAC mouse model, suggesting an extracellular vesicle–mediated RNA transfer mechanism that may remodel sensory signaling and open new prospects for diagnostic and therapeutic innovation in PDAC. Impact statement Transcriptomic proﬁling of pancreatic sensory neurons reveals shifts in neuronal populations, tumor-speciﬁc mitochondrial gene upregulation, and potential extracellular vesicle–mediated transcript transfer. Circulating Abbreviations 50 UTR, untranslated region; DRG, dorsal root ganglia; EVs, extracellular vesicles; FB, Fast Blue; IF, immunoﬂuorescence; KPC, Kras TrP53 Cre; LncRNA, long non-coding RNA; NF, neuroﬁlament containing; NP, non-peptidergic; PDAC, pancreatic ductal adenocarcinoma; PEP, peptidergic; ScRNA-seq, single-cell RNA sequencing; TH, tyrosine hydroxylase; WT, wild type. 1726 Molecular Oncology 20 (2026) 1726–1741 ª 2026 The Author(s) . Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access arti

FAQs

How were pancreatic sensory neurons identified in the study?

Wild-type and PDAC mice received Fast Blue retrotracer injections into pancreatic or cancerous tissue. Dorsal root ganglia were dissociated, and Fast Blue-positive sensory neurons were isolated for analysis.

Which sensory neuron subtype predominated under normal and tumor conditions?

Neurofilament-containing neurons were identified as the predominant sensory subtype in both normal and PDAC-associated innervation.

What evidence supports a mechanism of tumor–neuron interaction?

The study found transcripts transferred via extracellular vesicles, including those linked to the Pdx1-CreERT2 transgene in the KPC model, suggesting extracellular vesicle–mediated RNA transfer that could remodel sensory signaling.

Sep 22, 2026

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