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• Høye, Eirik; Kanduri, Chakravarthi; Kristensen, Annette Torgunrud; Lorenz, Susanne; Edwin, Bjørn von Gohren & Larsen, Stein Gunnar [Show all 10 contributors for this article] (2025). Enrichment of Cancer-Associated Fibroblasts, Macrophages, and Up-Regulated TNF-α Signaling in the Tumor Microenvironment of CMS4 Colorectal Peritoneal Metastasis. Cancer Medicine. 14(1). doi: 10.1002/cam4.70521. Full text in Research Archive Show summary

  Background Metastatic colorectal cancer (mCRC) is the main cause of CRC mortality, with limited treatment options. Although immunotherapy has benefited some cancer patients, mCRC typically lacks the molecular features that respond to this treatment. However, recent studies indicate that the immune microenvironment of mCRC may be modified to enhance the effect of immune checkpoint inhibitors. This study aimed to explore the metastatic tumor microenvironment (TME) by comparing cell populations in colorectal liver (CLM), lung (mLu), and peritoneal (PM) metastases. Methods RNA isolated from 20 CLM, 15 mLu, and 35 PM samples was subjected to mRNA sequencing and explored through TME deconvolution tools, consensus molecular subtyping (CMS), and differential gene expression and gene set enrichment analysis, with respect to the metastatic sites. Clinical data and KRAS/BRAF hotspot mutation status were also obtained for all the cases. Results The cell type fractions in the TME were relatively similar between the metastatic sites, except for cancer-associated fibroblasts (CAFs), B cells, endothelial cells, and CD4+ T cells. Notably, PM showed enrichment for CAFs and endothelial cells, consistent with distinct pathways associated with metastatic growth and progression in the peritoneal cavity. PM with the mesenchymal subtype, CMS4, had increased CAFs, endothelial cells, and macrophages, along with up-regulated genes related to TNF-α signaling via NF-κB, EMT, and angiogenesis. Conclusions Tumor samples from different metastatic sites exhibited a broadly similar TME in terms of immune cell composition, with some intriguing differences. Targeting CAF-associated pathways, macrophages, and TNF-α signaling through NR4A could represent potential novel therapeutic approaches in CMS4 PM.

• Clarke, Alexander W.; Høye, Eirik; Hembrom, Anju Angelina; Paynter, Vanessa Molin; Vinther, Jakob & Wyrozemski, Lukasz [Show all 22 contributors for this article] (2025). MirGeneDB 3.0: Improved taxonomic sampling, uniform nomenclature of novel conserved microRNA families and updated covariance models. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(D1), p. D116–D128. doi: 10.1093/nar/gkae1094. Full text in Research Archive
• Schiffer, Philipp H.; Natsidis, Paschalis; Leite, Daniel J.; Robertson, Helen E.; Lapraz, François & Marlétaz, Ferdinand [Show all 20 contributors for this article] (2024). Insights into early animal evolution from the genome of the xenacoelomorph worm Xenoturbella bocki. eLIFE. 13. doi: 10.7554/eLife.94948. Full text in Research Archive Show summary

  The evolutionary origins of Bilateria remain enigmatic. One of the more enduring proposals highlights similarities between a cnidarian-like planula larva and simple acoel-like flatworms. This idea is based in part on the view of the Xenacoelomorpha as an outgroup to all other bilaterians which are themselves designated the Nephrozoa (protostomes and deuterostomes). Genome data can provide important comparative data and help understand the evolution and biology of enigmatic species better. Here, we assemble and analyze the genome of the simple, marine xenacoelomorph Xenoturbella bocki, a key species for our understanding of early bilaterian evolution. Our highly contiguous genome assembly of X. bocki has a size of ~111 Mbp in 18 chromosome-like scaffolds, with repeat content and intron, exon, and intergenic space comparable to other bilaterian invertebrates. We find X. bocki to have a similar number of genes to other bilaterians and to have retained ancestral metazoan synteny. Key bilaterian signaling pathways are also largely complete and most bilaterian miRNAs are present. Overall, we conclude that X. bocki has a complex genome typical of bilaterians, which does not reflect the apparent simplicity of its body plan that has been so important to proposals that the Xenacoelomorpha are the simple sister group of the rest of the Bilateria.

• Ree, Anne Hansen; Høye, Eirik; Esbensen, Qin Ying; Beitnes, Ann-Christin Røberg; Negård, Anne & Bernklev, Linn [Show all 16 contributors for this article] (2024). Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade. Oncoimmunology. ISSN 2162-4011. 13(1). doi: 10.1080/2162402X.2024.2372886. Full text in Research Archive Show summary

  The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2–11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20–35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.

• Høye, Eirik; Dagenborg, Vegar Johansen; Kristensen, Annette Torgunrud; Lund-Andersen, Christin; Fretland, Åsmund Avdem & Lorenz, Susanne [Show all 13 contributors for this article] (2023). T cell receptor repertoire sequencing reveals chemotherapy-driven clonal expansion in colorectal liver metastases. GigaScience. 12. doi: 10.1093/gigascience/giad032. Full text in Research Archive Show summary

  Background - Colorectal liver metastasis (CLM) is a leading cause of colorectal cancer mortality, and the response to immune checkpoint inhibition (ICI) in microsatellite-stable CRC has been disappointing. Administration of cytotoxic chemotherapy may cause increased density of tumor-infiltrating T cells, which has been associated with improved response to ICI. This study aimed to quantify and characterize T-cell infiltration in CLM using T-cell receptor (TCR) repertoire sequencing. Eighty-five resected CLMs from patients included in the Oslo CoMet study were subjected to TCR repertoire sequencing. Thirty-five and 15 patients had received neoadjuvant chemotherapy (NACT) within a short or long interval, respectively, prior to resection, while 35 patients had not been exposed to NACT. T-cell fractions were calculated, repertoire clonality was analyzed based on Hill evenness curves, and TCR sequence convergence was assessed using network analysis.<p> <p>Results - Increased T-cell fractions (10.6% vs. 6.3%) were detected in CLMs exposed to NACT within a short interval prior to resection, while modestly increased clonality was observed in NACT-exposed tumors independently of the timing of NACT administration and surgery. While private clones made up >90% of detected clones, network connectivity analysis revealed that public clones contributed the majority of TCR sequence convergence.<p> <p>Conclusions - TCR repertoire sequencing can be used to quantify T-cell infiltration and clonality in clinical samples. This study provides evidence to support chemotherapy-driven T-cell clonal expansion in CLM in a clinical context.

• Fromm, Bastian; Høye, Eirik; Domanska, Diana; Zhong, Xiangfu; Aparicio-Puerta, Ernesto & Ovchinnikov, Vladimir [Show all 18 contributors for this article] (2022). MirGeneDB 2.1: toward a complete sampling of all major animal phyla. Nucleic Acids Research (NAR). ISSN 0305-1048. 50(D1), p. D204–D210. doi: 10.1093/nar/gkab1101. Full text in Research Archive Show summary

  We describe an update of MirGeneDB, the manually curated microRNA gene database. Adhering to uniform and consistent criteria for microRNA annotation and nomenclature, we substantially expanded MirGeneDB with 30 additional species representing previously missing metazoan phyla such as sponges, jellyfish, rotifers and flatworms. MirGeneDB 2.1 now consists of 75 species spanning over ∼800 million years of animal evolution, and contains a total number of 16 670 microRNAs from 1549 families. Over 6000 microRNAs were added in this update using ∼550 datasets with ∼7.5 billion sequencing reads. By adding new phylogenetically important species, especially those relevant for the study of whole genome duplication events, and through updating evolutionary nodes of origin for many families and genes, we were able to substantially refine our nomenclature system. All changes are traceable in the specifically developed MirGeneDB version tracker. The performance of read-pages is improved and microRNA expression matrices for all tissues and species are now also downloadable. Altogether, this update represents a significant step toward a complete sampling of all major metazoan phyla, and a widely needed foundation for comparative microRNA genomics and transcriptomics studies. MirGeneDB 2.1 is part of RNAcentral and Elixir Norway, publicly and freely available at http://www.mirgenedb.org/.

• Høye, Eirik; Fromm, Bastian; Böttger, Paul H.M.; Domanska, Diana; Kristensen, Annette Torgunrud & Lund-Andersen, Christin [Show all 13 contributors for this article] (2022). A comprehensive framework for analysis of microRNA sequencing data in metastatic colorectal cancer. NAR Cancer. 4(1), p. 1–13. doi: 10.1093/narcan/zcab051. Full text in Research Archive Show summary

  Although microRNAs (miRNAs) contribute to all hallmarks of cancer, miRNA dysregulation in metastasis remains poorly understood. The aim of this work was to reliably identify miRNAs associated with metastatic progression of colorectal cancer (CRC) using novel and previously published nextgeneration sequencing (NGS) datasets generated from 268 samples of primary (pCRC) and metastatic CRC (mCRC; liver, lung and peritoneal metastases) and tumor adjacent tissues. Differential expression analysis was performed using a meticulous bioinformatics pipeline, including only bona fide miRNAs, and utilizing miRNA-tailored quality control and processing. Five miRNAs were identified as upregulated at multiple metastatic sites Mir-210 3p, Mir191 5p, Mir-8-P1b 3p [mir-141–3p], Mir-1307 5p and Mir-155 5p. Several have previously been implicated in metastasis through involvement in epithelial-tomesenchymal transition and hypoxia, while other identified miRNAs represent novel findings. The use of a publicly available pipeline facilitates reproducibility and allows new datasets to be added as they become available. The set of miRNAs identified here provides a reliable starting-point for further research into the role of miRNAs in metastatic progression.

• Kang, Wenjing; Fromm, Bastian; Houben, Anna J.; Høye, Eirik; Bezdan, Daniela & Arnan, Carme [Show all 11 contributors for this article] (2021). MapToCleave: High-throughput profiling of microRNA biogenesis in living cells. Cell reports. 37(7). doi: 10.1016/j.celrep.2021.110015. Full text in Research Archive Show summary

  Previous large-scale studies have uncovered many features that determine the processing of microRNA (miRNA) precursors; however, they have been conducted in vitro. Here, we introduce MapToCleave, a method to simultaneously profile processing of thousands of distinct RNA structures in living cells. We find that miRNA precursors with a stable lower basal stem are more efficiently processed and also have higher expression in vivo in tissues from 20 animal species. We systematically compare the importance of known and novel sequence and structural features and test biogenesis of miRNA precursors from 10 animal and plant species in human cells. Lastly, we provide evidence that the GHG motif better predicts processing when defined as a structure rather than sequence motif, consistent with recent cryogenic electron microscopy (cryo-EM) studies. In summary, we apply a screening assay in living cells to reveal the importance of lower basal stem stability for miRNA processing and in vivo expression.

• Dagenborg, Vegar Johansen; Marshall, Serena; Yaqub, Sheraz; Grzyb, Krzysztof; Pedersen, Kjetil Boye & Lund-Iversen, Marius [Show all 12 contributors for this article] (2020). Neoadjuvant chemotherapy is associated with a transient increase of intratumoral T-cell density in microsatellite stable colorectal liver metastases. Cancer Biology & Therapy. ISSN 1538-4047. 21(5), p. 432–440. doi: 10.1080/15384047.2020.1721252. Full text in Research Archive Show summary

  Patients with colorectal liver metastases (CLM) commonly receive neoadjuvant chemotherapy (NACT) prior to surgical resection. NACT may induce immunogenic cell death with subsequent recruitment of T-cells to the tumor microenvironment, which could be exploited by immune checkpoint inhibition (ICI). In theory, this could expand the use of ICI to obtain responses also in microsatellite stable colorectal cancer, but evidence to suggest optimal treatment schedules are lacking. In this study, densities of total-, cytotoxic-, helper- and regulatory T-cells were quantified by immunohistochemistry in resected CLM from 92 patients included in the OSLO-COMET trial (NCT01516710). All but one patient had microsatellite stable tumors (91/92). Associations between T-cell densities and clinicopathological parameters were analyzed. Fluoropyrimidine-based NACT (in most cases with addition of oxaliplatin or irinotecan) was administered to 45 patients completed median 8 weeks prior to surgical resection. No overall association was found between NACT administration and intratumoral T-cell densities. However, within the NACT group, a short time interval (<9.5 weeks) between NACT completion and CLM resection was strongly associated with high intratumoral T-cell densities compared to the long-interval and no NACT groups (medians 491, 236, and 292 cells/mm2, respectively; P < .0001). The results from this study suggest that the observed increase in intratumoral T-cells after NACT administration may be transient. The significance of this finding should be further explored to ensure that optimal treatment schedules are chosen for studies combining cytotoxic chemotherapy and ICI.

• Fromm, Bastian; Domanska, Diana Ewa; Høye, Eirik; Ovchinnikov, Vladimir; Kang, Wenjing & Aparicio-Puerta, Ernesto [Show all 13 contributors for this article] (2019). MirGeneDB 2.0: the metazoan microRNA complement. Nucleic Acids Research (NAR). ISSN 0305-1048. 48(D1), p. D132–D141. doi: 10.1093/nar/gkz885. Full text in Research Archive Show summary

  Small non-coding RNAs have gained substantial attention due to their roles in animal development and human disorders. Among them, microRNAs are special because individual gene sequences are conserved across the animal kingdom. In addition, unique and mechanistically well understood features can clearly distinguish bona fide miRNAs from the myriad other small RNAs generated by cells. However, making this distinction is not a common practice and, thus, not surprisingly, the heterogeneous quality of available miRNA complements has become a major concern in microRNA research. We addressed this by extensively expanding our curated microRNA gene database - MirGeneDB - to 45 organisms, encompassing a wide phylogenetic swath of animal evolution. By consistently annotating and naming 10,899 microRNA genes in these organisms, we show that previous microRNA annotations contained not only many false positives, but surprisingly lacked &amp;gt;2000 bona fide microRNAs. Indeed, curated microRNA complements of closely related organisms are very similar and can be used to reconstruct ancestral miRNA repertoires. MirGeneDB represents a robust platform for microRNA-based research, providing deeper and more significant insights into the biology and evolution of miRNAs as well as biomedical and biomarker research. MirGeneDB is publicly and freely available at http://mirgenedb.org/.

• Fromm, Bastian; Ovchinnikov, Vladimir Y.; Høye, Eirik; Bernal, Dolores; Hackenberg, Michael & Marcilla, Antonio (2017). On the presence and immunoregulatory functions of extracellular microRNAs in the trematode Fasciola hepatica. Parasite immunology (Print). ISSN 0141-9838. 39:e12399(2), p. 1–9. doi: 10.1111/pim.12399. Full text in Research Archive

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• Fromm, Bastian; Domanska, Diana; Høye, Eirik; Ovchinnikov, Vladimir; Kang, Wenjing & Aparicio-Puerta, Ernesto [Show all 13 contributors for this article] (2020). Erratum: MirGeneDB 2.0: The metazoan microRNA complement (Nucleic Acids Research (2019) DOI: 10.1093/nar/gkz885). Nucleic Acids Research (NAR). ISSN 0305-1048. 48(1), p. D1172–D1172. doi: 10.1093/nar/gkz1016. Full text in Research Archive

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