2. Academic Validation
  3. The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer

The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer

  • bioRxiv. 2025 Aug 31:2025.08.26.672505. doi: 10.1101/2025.08.26.672505.
Peter Wang,  Nicole Lester,  Ella Perrault,  Jennifer Su,  Dennis Gong,  Carina Shiau,  Jingyi Cao,  Phuong Nguyen,  Jung Woo Bae,  Deniz Olgun,  Hannah Hoffman,  Ashley Lam,  Jean Huang-Gao,  Saifur Rahaman,  Jimmy Guo,  Jaimie Barth,  Nicholas Caldwell,  Prajan Divakar,  Jason Reeves,  Arya Bahrami,  Shanshan He,  Michael Patrick,  Eric Miller,  Maria Ganci,  Grissel Cervantes-Jaramillo,  Theodore Hong,  Jennifer Wo,  Hannah Roberts,  Ralph Weissleder,  Hongyoon Choi,  Carlos Fernandez-Del-Castillo,  Kathy Cormier,  David T Ting,  Tyler Jacks,  Lei Zheng,  Martin Hemberg,  Mari Mino-Kenudson,  William L Hwang
PMID: 40909696 DOI: 10.1101/2025.08.26.672505
Abstract

Nerves are an integral component of the tumor microenvironment, contributing to Cancer progression, metastasis, morbidity, and mortality. In pancreatic ductal adenocarcinoma (PDAC), worse clinical outcomes are associated with perineural invasion (PNI), a process by which Cancer cells surround and invade nerves. Here, we employed whole-transcriptome and single-cell spatial transcriptomics to identify candidate tumor-nerve interactions that promote PNI. We discovered that Pdgfd signaling promotes key features of nerve invasion. Mechanistically, Pdgfd stimulated Cancer cell invasiveness, neurite outgrowth, and direct physical engagement with glia. Pharmacological blockade of this axis reduced each of these processes in vitro as well as PNI in vivo. Thus, Pdgfd-Pdgfrb signaling mediates PNI by coordinating multifaceted cancer-neuron-glia interactions and represents a promising therapeutic strategy aimed at disrupting harmful cancer-nerve crosstalk.

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