Spatial Transcriptomics Reveals Novel Mechanisms Involved in Perineural Invasion in Pancreatic Ductal Adenocarcinomas
by
, , , ,
Vanessa Lakis
1
,
Noni L Chan
2,
Ruth Lyons
3,
Nicola Blackburn
3,
Tam Hong Nguyen
1,
Crystal Chang
1,
Andrew Masel
1,
Nicholas P. West
4,
Glen M. Boyle
1,5,6,
Ann-Marie Patch
1,
Anthony J. Gill
2,3,7,8 and
Katia Nones
1,5,9,* 1
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
2
NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia
3
Australian Pancreatic Cancer Genome Initiative (APGI), Kinghorn Cancer Centre, Sydney, NSW 2010, Australia
4
Griffith Health, Griffith University, Gold Coast, QLD 4215, Australia
5
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
6
School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Kelvin Grove, QLD 4000, Australia
7
Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia
8
Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW 2065, Australia
9
Faculty of Health, Medicine and Behavioural Sciences/PA Southside Clinical Unit, The University of Queensland, Brisbane, QLD 4102, Australia
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(5), 852; https://doi.org/10.3390/cancers17050852
Submission received: 28 January 2025
/
Revised: 24 February 2025
/
Accepted: 27 February 2025
/
Published: 1 March 2025
(This article belongs to the Special Issue Tumor Microenvironment: Intercellular Communication)
Simple Summary
Pancreatic cancer has a low survival rate with limited treatment options. Perineural invasion (PNI), where cancer cells infiltrate the nerves in the pancreas, is associated with a poor prognosis and local recurrence. Pancreatic cancer is one of the most painful cancers, with PNI contributing to the pain experienced by patients. However, the mechanisms involved in the cancer invasion of nerves are not completely understood. Here, we used spatial transcriptomics to study the expression of both cancer and nerve cells in microscopic regions of PNI and compared it to regions without PNI evidence to better understand the mechanisms involved in PNI. We identified novel mechanisms that may impact cancer growth, PNI and pain experienced by patients.
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) has a high incidence of perineural invasion (PNI), a pathological feature of the cancer invasion of nerves. PNI is associated with a poor prognosis, local recurrence and cancer pain. It has been suggested that interactions between nerves and the tumor microenvironment (TME) play a role in PDAC tumorigenesis. Methods: Here, we used Nanostring GeoMx Digital Spatial Profiler to analyze the whole transcriptome of both cancer and nerve cells in the microenvironment of PNI and non-PNI foci from 13 PDAC patients. Conclusions: We identified previously reported pathways involved in PNI, including Axonal Guidance and ROBO-SLIT Signaling. Spatial transcriptomics highlighted the role of PNI foci in influencing the immune landscape of the TME and similarities between PNI and nerve injury response. This study revealed that endocannabinoid and polyamine metabolism may contribute to PNI, cancer growth and cancer pain. Key members of these pathways can be targeted, offering potential novel research avenues for exploring new cancer treatment and/or pain management options in PDAC.
Keywords:
perineural invasion; spatial transcriptomics; MGLL; SAT1; nerve; pain
