Research Papers:

Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases

Olga Østrup, Vegar Johansen Dagenborg, Einar Andreas Rødland, Veronica Skarpeteig, Laxmi Silwal-Pandit, Krzysztof Grzyb, Audun Elnæs Berstad, Åsmund Avdem Fretland, Gunhild Mari Mælandsmo, Anne-Lise Børresen-Dale, Anne Hansen Ree, Bjørn Edwin, Vigdis Nygaard and Kjersti Flatmark _

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Oncotarget. 2017; 8:76290-76304. https://doi.org/10.18632/oncotarget.19350

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Olga Østrup1,2,*, Vegar Johansen Dagenborg1,9,*, Einar Andreas Rødland1,2, Veronica Skarpeteig2, Laxmi Silwal-Pandit2, Krzysztof Grzyb5, Audun Elnæs Berstad7, Åsmund Avdem Fretland4,8,9, Gunhild Mari Mælandsmo1,10, Anne-Lise Børresen-Dale2,9, Anne Hansen Ree6,9, Bjørn Edwin4,8,9, Vigdis Nygaard1,* and Kjersti Flatmark1,3,9,*

1Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway

2Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway

3Department of Gastroenterological Surgery, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway

4Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway

5Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway

6Department of Oncology, Akershus University Hospital, Lørenskog, Norway

7Department of Radiology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway

8The Intervention Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway

9Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

10Department of Pharmacy, University of Tromsø - The Arctic University of Norway, Tromsø, Norway

*These authors have contributed equally to this work

Correspondence to:

Kjersti Flatmark, email: [email protected]

Keywords: colorectal liver metastases, genomic profiling, neoadjuvant chemotherapy, immunogenic cell death

Received: February 23, 2017    Accepted: June 26, 2017    Published: July 18, 2017


Background: Metastatic colorectal cancer (CRC) is associated with highly variable clinical outcome and response to therapy. The recently identified consensus molecular subtypes (CMS1-4) have prognostic and therapeutic implications in primary CRC, but whether these subtypes are valid for metastatic disease is unclear. We performed multi-level analyses of resectable CRC liver metastases (CLM) to identify molecular characteristics of metastatic disease and evaluate the clinical relevance.

Methods: In this ancillary study to the Oslo-CoMet trial, CLM and tumor-adjacent liver tissue from 46 patients were analyzed by profiling mutations (targeted sequencing), genome-wide copy number alteration (CNAs), and gene expression.

Results: Somatic mutations and CNAs detected in CLM were similar to reported primary CRC profiles, while CNA profiles of eight metastatic pairs suggested intra-patient divergence. A CMS classifier tool applied to gene expression data, revealed the cohort to be highly enriched for CMS2. Hierarchical clustering of genes with highly variable expression identified two subgroups separated by high or low expression of 55 genes with immune-related and metabolic functions. Importantly, induction of genes and pathways associated with immunogenic cell death (ICD) was identified in metastases exposed to neoadjuvant chemotherapy (NACT).

Conclusions: The uniform classification of CLM by CMS subtyping may indicate that novel class discovery approaches need to be explored to uncover clinically useful stratification of CLM. Detected gene expression signatures support the role of metabolism and chemotherapy in shaping the immune microenvironment of CLM. Furthermore, the results point to rational exploration of immune modulating strategies in CLM, particularly by exploiting NACT-induced ICD.

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