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Pancreatic ductal adenocarcinoma induces neural injury that promotes a transcriptomic and functional repair signature by peripheral neuroglia

Oncogene volume 42, pages 2536–2546 (2023)Cite this article

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Abstract

Perineural invasion (PNI) is the phenomenon whereby cancer cells invade the space surrounding nerves. PNI occurs frequently in epithelial malignancies, but is especially characteristic of pancreatic ductal adenocarcinoma (PDAC). The presence of PNI portends an increased incidence of local recurrence, metastasis and poorer overall survival. While interactions between tumor cells and nerves have been investigated, the etiology and initiating cues for PNI development is not well understood. Here, we used digital spatial profiling to reveal changes in the transcriptome and to allow for a functional analysis of neural-supportive cell types present within the tumor-nerve microenvironment of PDAC during PNI. We found that hypertrophic tumor-associated nerves within PDAC express transcriptomic signals of nerve damage including programmed cell death, Schwann cell proliferation signaling pathways, as well as macrophage clearance of apoptotic cell debris by phagocytosis. Moreover, we identified that neural hypertrophic regions have increased local neuroglial cell proliferation which was tracked using EdU tumor labeling in KPC mice, as well as frequent TUNEL positivity, suggestive of a high turnover rate. Functional calcium imaging studies using human PDAC organotypic slices confirmed nerve bundles had neuronal activity, as well as contained NGFR+ cells with high sustained calcium levels, which are indicative of apoptosis. This study reveals a common gene expression pattern that characterizes solid tumor-induced damage to local nerves. These data provide new insights into the pathobiology of the tumor-nerve microenvironment during PDAC as well as other gastrointestinal cancers.

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Fig. 1: Digital spatial profiling of the tumor-nerve microenvironment in KPC mice reveals transcriptomic upregulation of apoptotic processes and JUN signaling gene signatures.
Fig. 2: Nerve associated macrophage enriched regions express gene signatures involved in phagocytosis.
Fig. 3: Proliferation of local neuroglia in the tumor nerve microenvironment.
Fig. 4: Neural injury and non-myelinating Schwann cell signatures identified in murine transcriptomic analysis are expressed in human PDAC and gastrointestinal tumors.
Fig. 5: Functional imaging of the tumor nerve microenvironment using organotypic tumor slices from human PDAC donor resections.

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Data availability

Raw data for this study were generated at the University of California, San Diego Moores by the Sandip Patel Lab (https://moorescancercenter.ucsd.edu/research/centers-and-labs/patel-lab/index.html). Derived data supporting the findings of this study are available from the corresponding author upon request.

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Funding

This work was supported by a grant from the National Cancer Institute, 1F32CA265052-01 (JRW). Confocal imaging and histology core was done with support from the UCSD Specialized Cancer Support Center P30 grant 2P30CA023100. We would like to thank Chandra Inglis and Karthik Ramesh from the Patel lab for their expert assistance in using the GeoMx Nanostring instrument and bioinformatics processing.

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Authors and Affiliations

  1. Department of Surgery, University of California, San Diego, La Jolla, CA, CA 92093, USA

    Jonathan Weitz, Bharti Garg, Alexei Martsinkovskiy, Herve Tiriac & Andrew M. Lowy

  2. Division of Hematology-Oncology in the Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA

    Sandip Patel

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Contributions

Conceptualization: JRW, AML. Methodology: JRW, BG, HT, SP, AML. Investigation: JRW, BG, HT, AML. Funding acquisition: JRW, AML. Writing— original draft: JRW. Writing— review & editing: JW, HT, SP, AML.

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Weitz, J., Garg, B., Martsinkovskiy, A. et al. Pancreatic ductal adenocarcinoma induces neural injury that promotes a transcriptomic and functional repair signature by peripheral neuroglia. Oncogene 42, 2536–2546 (2023). https://doi.org/10.1038/s41388-023-02775-7

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