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Gut. 2019 Jan 18. pii: gutjnl-2018-317706. doi: 10.1136/gutjnl-2018-317706. [Epub ahead of print]

Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes.

Author information

1
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
2
Department of Medicine, Division of Digestiveand Liver Diseases, Columbia University Medical Center, New York, New York, USA.
3
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.
4
Department of Biomedical Informatics, Columbia Unicersity Medical Center, New York, New York, USA.
5
Department Systems Biology, Columbia University Medical Center, New York, New York, USA.
6
Department of Surgery, Division of GI/EndocrineSurgery, Columbia University Medical Center, New York, New York, USA.
7
Department of Medicine, Division of Hematology and Oncology, New York University Langone Medical Center, New York, New York, USA.
8
Department of Epidemiology, Mailman School of Public Health, New York, New York, USA.
9
Department of Computer Science and Engineering, University of California, San Diego, California, USA.
10
PsychoGenics Inc, Paramus, New Jersey, USA.
#
Contributed equally

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.

KEYWORDS:

pancreatic cancer

PMID:
30658994
DOI:
10.1136/gutjnl-2018-317706

Conflict of interest statement

Competing interests: AC is a founder and shareholder of DarwinHealth Inc. and a member of the Tempus Inc. SAB and shareholder. Columbia University is a shareholder of DarwinHealth Inc. KPO is a member of the SAB for Elstar Therapeutics.

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