Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes.
Carlo Maurer, Sam R Holmstrom, Jing He, Pasquale Laise, Tao Su, Aqeel Ahmed, Hanina Hibshoosh, John A Chabot, Paul E Oberstein, Antonia R Sepulveda, Jeanine M Genkinger, Jiapeng Zhang, Alina C Iuga, Mukesh Bansal, Andrea Califano, Kenneth P Olive
Author Information
Carlo Maurer: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Sam R Holmstrom: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Jing He: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Pasquale Laise: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Tao Su: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Aqeel Ahmed: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Hanina Hibshoosh: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
John A Chabot: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Paul E Oberstein: Department of Medicine, Division of Hematology and Oncology, New York University Langone Medical Center, New York, New York, USA.
Antonia R Sepulveda: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Jeanine M Genkinger: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Jiapeng Zhang: Department of Computer Science and Engineering, University of California, San Diego, California, USA.
Alina C Iuga: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Mukesh Bansal: PsychoGenics Inc, Paramus, New Jersey, USA.
Andrea Califano: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Kenneth P Olive: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA. ORCID
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) has among the highest stromal fractions of any cancer and this has 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.
