Cited by 220Pancreatic and Hepatic Oncology ResearchGene expression and cancer classificationCancer Genomics and Diagnostics

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Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes

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Maurer, Carlo, Holmstrom, Sam R, He, Jing, Laise, Pasquale, Su, Tao, Ahmed, Aqeel, Hibshoosh, Hanina, Chabot, John A, Oberstein, Paul E, Sepulveda, Antonia R, Genkinger, Jeanine M, Zhang, Jiapeng, Iuga, Alina C, Bansal, Mukesh, Califano, Andrea, Olive, Kenneth P·2019·Gut

DOI 10.1136/gutjnl-2018-317706PMC PMC6509007

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Abstract

Objective: Pancreatic ductal adenocarcinoma (PDA) has among the highest stromal fractions of any cancer and this has complicated attempts at expression-based molecular classification. The goal of this work is to profile purified samples of human PDA epithelium and stroma and examine their respective contributions to gene expression in bulk PDA samples. Design: We used laser capture microdissection (LCM) and RNA sequencing to profile the expression of 60 matched pairs of human PDA malignant epithelium and stroma samples. We then used these data to train a computational model that allowed us to infer tissue composition and generate virtual compartment-specific expression profiles from bulk gene expression cohorts. Results: Our analysis found significant variation in the tissue composition of pancreatic tumours from different public cohorts. Computational removal of stromal gene expression resulted in the reclassification of some tumours, reconciling functional differences between different cohorts. Furthermore, we established a novel classification signature from a total of 110 purified human PDA stroma samples, finding two groups that differ in the extracellular matrix-associated and immune-associated processes. Lastly, a systematic evaluation of cross-compartment subtypes spanning four patient cohorts indicated partial dependence between epithelial and stromal molecular subtypes. Conclusion: Our findings add clarity to the nature and number of molecular subtypes in PDA, expand our understanding of global transcriptional programmes in the stroma and harmonise the results of molecular subtyping efforts across independent cohorts.

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Authors: Maurer, C., Holmstrom, S. R., He, J., Laise, P., Su, T., Ahmed, A., Hibshoosh, H., Chabot, J. A., Oberstein, P. E., Sepulveda, A. R., Genkinger, J. M., Zhang, J., Iuga, A. C., Bansal, M., Califano, A., & Olive, K. P.
Affiliations: Columbia University Irving Medical Center (US)
NYU Langone Health (US)
University of California San Diego (US)
Psychogenics (United States) (US)
Corresponding author: Califano, Andrea
ORCID: He, Jing
Laise, Pasquale
Su, Tao
Hibshoosh, Hanina
Oberstein, Paul E
Sepulveda, Antonia R
Genkinger, Jeanine M
Zhang, Jiapeng
Iuga, Alina C
Bansal, Mukesh
Califano, Andrea
Olive, Kenneth P
Venue: Gut
Publisher: BMJ
Published: 2019-01-18
Volume: 68
Issue: 6
Pages: 1034-1043
ISSN: 0017-5749 (ISSN-L)
1468-3288
DOI: 10.1136/gutjnl-2018-317706
PMC: PMC6509007
OpenAlex: W2910033560
Cited by: 216
References: 27
Citations by year: 2026: 15 · 2025: 27 · 2024: 30 · 2023: 22 · 2022: 36 · 2021: 43 · 2020: 27 · 2019: 16
FWCI: 12.85
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Gut (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
HighWire Press Open Archive (submittedVersion)
Funders: National Institutes of Health
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: pancreatic ductal adenocarcinoma, tumor stroma, molecular subtypes, stromal gene expression, extracellular matrix, antitumor immunity
MeSH terms: Adenocarcinoma, Computer Simulation, Extracellular Matrix, Humans, Pancreatic Neoplasms, Sensitivity and Specificity, Gene Expression Regulation, Neoplastic, Case-Control Studies, Gene Expression Profiling, Carcinoma, Pancreatic Ductal, Microdissection

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Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes

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