Research Highlights 2013–2024

Basic studies:

Several groups have established and developed novel experimental models to do mechanistic studies and drug screening, such as organoids, PDX models, and the establishment of human cancer-derived cell lines (breast, endometrium, lung, ovary, prostate, vulva). Models of cancer-nerve interactions have been established. 

Examples: Preclinical CD37 and CA125 directed CAR-T have been established, and CD24-based fluorescence guided surgery is reported. For high-grade ovarian cancer and pancreatic cancer, a novel decellularized porcine tissue in vitro platform has been developed for experimental studies. A model for stepwise tumor development in prostate cancer is established, revealing a key IL-6/STAT3 differentiation loop and importance of transcription factors (AR, β-catenin). This model is used in drug screening, and the blocking of Wnt/β-catenin by axitinib is identified by drug repurposing. The relationship between Axl and immune responses and therapy resistance is focused in several projects. Studies have been performed on matrix biology and the α11 integrin molecule, a collagen receptor, including development of novel antibodies suitable for archival tissues and imaging mass cytometry (IMC), and an ITGA11-Cre mouse strain is developed. As an example of the emerging field of cancer neuroscience, models for studies of breast cancer cells interacting with neural cells are established, with the first study published.

Biomarker mapping: 

A large number of papers report on the discovery and validation of novel cancer biomarkers, using tissue samples or liquid biopsies, from clinical cohorts and trial studies. Such markers have been validated to show improved patient stratification by multivariate survival analyses.

Examples: Regarding solid cancers, extensive results have been presented on gynecologic and breast cancers, as well as some data on melanoma, oral cancer, and prostate tumors (Axl, breast cancer proteomic signatures, hypoxia markers, age signatures, HER2, immune-markers like FOXP3 T-cells, PD1-PDL1, TCR deep sequencing, and miR-204, MSH6, vimentin). Some of these markers have been examined or included in clinical trials. Indications of a new relationship between FOXP3 and response to immunotherapy in advanced melanoma have been observed, and a novel Axl isoform (Axl3) has been discovered. Data on breast cancer-neural interactions are published, showing induction of aggressive tumor features by neural cells. Also, new results on circulating biomarkers have been reported from trial studies (ctDNA, CTC).

Functional biomarkers in leukemia and lung cancer (single cell signaling mapping by mass cytometry; PD1-PDL1 by PLA, proximity Ligation Assay) have been reported. High-dimensional biomarker studies using Imaging Mass Cytometry (IMC) enabling single cell spatial analytics of the tissue landscape have been reported. In ovarian cancer trials, changes in multifunctional cytokines and immune response markers have been studied in preclinical models and reported as promising for treatment stratification. 

Clinical studies:

In addition to multiple clinical cohort studies (retrospective), CCBIO teams have organized or participated significantly in around 20 clinical trials, attempting to improve treatment and pre-treatment stratification by companion biomarkers.

Examples: In prostate cancer, the early CryoIT trial using cryo-immunotherapy for advanced prostate cancer, by dendritic cells, revealed responses and several promising predictive biomarkers (TCR deep sequencing, CTCs). Anti-Axl treatment is applied in several trials and shown to restore PD-1 blockade sensitivity of STK11/LKB1 mutant lung cancer (NSCLC) through expansion of TCF1+ CD8 T-cells. In advanced melanoma, anti-VEGF monotherapy has shown efficacy, with expression of beta-2 adrenergic receptors (β2-AR) indicating predictive value. Strong expression of Activin A, interleukin-1β, and urokinasetype plasminogen activator receptor in metastases, as well as vascular metrics, are significantly associated with overall response to bevacizumab in metastatic melanoma. In leukemia studies, single cell analysis of signaling circuits is reported as very promising functional biomarkers for early response prediction as a basis for adaptive treatment. 

Societal studies: 

Biomedical projects are integrated with ethics and economics research, focusing on how to fund and prioritize expensive cancer diagnostics and treatment, in a responsible way, in the era of expanding and costly personalized medicine. Economic evaluations of drug use and applied biomarkers are performed, also looking at models for drug reimbursement. Several papers and PhD theses have been produced. Societal studies contribute to self-reflection and intellectual awareness (ELSA/RRI) in the CCBIO environment.

Several of the projects have led to issued or pending patents, for example on prostate cancer (cryo-immunotherapy), breast cancer (stromal proteomics signatures), novel antibodies for diagnostic and therapeutic purposes (Axl, α11, NPM1), and drugs for leukemia. Regarding companies, some have been founded by CCBIO teams and collaborate with CCBIO: KinN Therapeutics (2004), tailored preclinical oncology services for the development of novel anticancer compounds; Alden Cancer Therapy AS (2013), dendritic cell immunotherapy combined with cryoablation against cancer; Hà Biotechnology AS (2019), nanobody design and production; Bjørgvin Therapeutics Group AS (2024), small molecule design, production, clinical development for cancer therapy. Several investigators have collaborated closely with BerGenBio, a clinical-stage biopharmaceutical company developing innovative drugs for aggressive diseases, including cancer.

From the start, science education and outreach have been important for CCBIO. The CCBIO Research School for Cancer Studies was established as the first research school focusing on cancer in Norway. Twelve core courses have been established, most of them being held annually or every second year, with topics ranging from biomarker methods to clinical trials, scientific writing and communication, innovation, as well as ethics and economics.

Also, a Masterclass program was established to mentor the most promising young scientists, with 10 candidates in each cycle. The research school has been widely acclaimed and appreciated by the students and is open to all students at UiB and outside. All courses have also been opened up as ECTS-giving courses for master level students, and for the general scientific public for attendance and transfer of knowledge without ECTS, thereby ensuring maximum output.

CCBIO has been very active in public dissemination with more than 500 media appearances, e.g. in commentaries and interviews in newspapers and television, as well as more than 250 popularized presentations and events, e.g. a multi-year theatre-based program in cancer biology for school children.

In addition to more than 1000 publications, CCBIO has published the following books: 2017: Roger Strand, Anne Blanchard (eds): Cancer Biomarkers: Ethics, Economics and Society. 2017: Lars A. Akslen, Randolph S. Watnick (eds): Biomarkers of the Tumor Microenvironment - Basic Studies and Practical Applications, Springer. 2022: Anne Blanchard and Roger Strand (eds): Precision Oncology and Cancer Biomarkers: Issues at Stake and Matters of Concern, Springer. 2022: Lars A. Akslen and Randolph S. Watnick (eds): Biomarkers of the Tumor Microenvironment, Springer (2nd ed., textbook).

CCBIO established from the beginning a framework of various meetings: monthly research seminars with invited speakers mainly from abroad, special seminars with guest presentations (e.g. by visiting opponents), annual symposia in May each year (international meeting, 200–250 participants), four junior scientist symposia per year (organized and chaired by postdocs and young researchers), and mini-symposia (2–3 presentations with panel discussion). The annual symposia have been especially valued, being a high-density research meeting with time for crosstalk and bonding as a basis for novel collaborations.

In addition to CCBIO-internal meetings, researchers have been active in organizing external meetings, such as the P53 isoforms conference, Bergen (2017), and the Nordic AML meeting, Bergen (2023). In 2016, Akslen & Östman founded the SCANPATH meeting, a network gathering for pathology-based researchers using tissues and novel techniques, with annual meetings (80–120 participants) and increasing collaboration. As a collaboration with the Vascular Biology Program and Harvard Medical School (Boston), two meetings have been organized (the CCBIO–VBP Research Meetings; 2019, 2024).

CCBIO researchers have received multiple awards over the years, for example for presentations at meetings and congresses. In 2021, Gjertsen was awarded the King Olav V Cancer Research Prize. In 2023, Akslen received the Helse Vest Research Award (second time). In 2023, Norheim was awarded a CoE from the RCN: Bergen Centre for Ethics and Priority Setting in Health (BCEPS), and in 2024, Gjertsen was awarded a five-year KG Jebsen Centre for Myeloid Blood Cancer (C-MYC). The following CCBIO researchers were elected members to the Norwegian Academy of Science and Letters: James Lorens 2020, Ole Frithjof Norheim 2021, and Inge Jonassen 2021. From before, Lars A. Akslen and Rolf Reed are also members. Akslen was elected to Academia Europaea in 2023.

Gullberg group: The Matrix Biology Group 

The group has consistently focused on the role of α11β1 integrin in various aspects of extracellular matrix and stroma remodeling in malignant tumors, particular cell-collagen interactions. Further, the group has focused on experimental models, with development and characterization of several novel α11-antibodies and the new fibroblast specific transgenic Cre driver mouse (ITGA11-Cre) strain. Gullberg and collaborators have recently shown how α11 can influence fibroblast migration, as well as proliferation and invasion in malignant tumors (Zeltz et al., Cancers 2019; Erusappan et al., Sci Rep 2019). The clinical relevance of α11 integrin expression has been reported (Smeland et al., J Pathol Clin Res 2020).

Kalland group: The Cancer Immunotherapy Research Group

The group initially focused on understanding prostate cancer development and characteristics, by establishing experimental models, and novel molecular mechanisms of benign prostate basal to luminal cell differentiation were discovered, particularly related to the expression of the androgen receptor (AR) and its target genes. A stepwise prostate tumorigenesis model was then developed without carcinogen use, identifying tumorigenic cells characterized by an IL-6/STAT3 regulatory loop (Qu et al., Cancer Res 2013). This model was used in drug discovery, identifying small molecular compounds that inhibit the transcription factors AR, β-catenin, and STAT3 (Qu et al., PNAS 2016; Qu et al., Nature Chem Biol 2018). In a different line of investigation, Kalland and collaborators organized and conducted an early clinical trial of cryoimmunotherapy for advanced prostate cancer (CryoIT), showing promising clinical response and novel biomarkers (Thomsen et al., Cancer Immunol Immunother 2023).

Mc Cormack group: The PreCOS (Precision Oncology) Group

The team’s core activities focus on the establishment and application of clinically relevant experimental models (PDX, Hu-PDX, in vitro decellularized scaffold platforms) integrated with multimodal molecular imaging strategies. Recently, the group has concentrated on the development of novel immunotherapies (CAR-T and BiTes). The team also reported a novel Axl3 isoform as a potential game changer in the function, localization, and regulation of Axl in cancer (Gelebart et al., Blood 2023). In the team’s work on CD37 targeted CAR-T, they demonstrate the preclinical efficacy and superiority in AML versus other CAR concepts currently in clinical development. Therapy improvements for ovarian cancer by CD24-targeted intraoperative fluorescence image-guided surgery have also been reported (Kleinmanns et al., eBioMedicine 2020).

Akslen group: The Cancer Biomarker Group

During the last 10–12 years, the group has mainly focused on proteomics studies of breast cancer, particularly related to the tumor microenvironment, performed by mass spectrometry (whole tissues) and the multidimensional imaging mass cytometry technique (tissue slides). The aim has been to discover and validate novel tissue-based cancer biomarkers for improved molecular grading and patient stratification. The group has reported novel and strong hypoxia-related proteomic signatures of breast cancer stroma (Kjølle et al., Nat Commun 2023). Lately, the group has focused on the growing field of cancer neuroscience and reported mutual effects between cancer cells and neural elements of clinical relevance (Bjørnstad et al., eBioMedicine 2023; Wik et al., in revision 2024). The role of PRSS2 and Stathmin in regulation of immune response has been published (Sui et al., Nat Commun 2022; Askeland et al., Sci Rep 2020). 

Costea group: The Experimental Pathology Research Group

The group has focused on experimental models for tumorfibroblast interactions and characterization of fibroblast subgroups. Oral tumors, stratified for HPV-status, and the relationship with vulvar tumors, have been examined in later comparative studies. The identification of two distinct carcinoma-associated fibroblast subtypes with differential roles was reported (Costea et al., Cancer Res 2013). It was further published that metabolic reprogramming of normal oral fibroblasts correlated with increased metabolic changes of oral squamous cell carcinoma, preceding their conversion to carcinoma associated fibroblasts (Zhang et al., Cell Mol Life Sci 2020). Also, a role of miRNA-204 in regulating invasion was reported from studies of CAFs in oral cancer (Rajthala et al., Int J Mol Sci 2021).

Engelsen group: Cancer Cell Plasticity and Therapy Resistance Group

The group has been focusing on exploring how phenotypic plasticity interferes with therapeutic efficacy and immune cell-mediated tumor cell killing. They reported how Axl targeting abrogates autophagic flux and induces immunogenic cell death (Lotsberg et al., J Thoracic Oncol 2020). Further, the importance of Axl as a driver of stemness in normal mammary gland and breast cancer was presented (Engelsen et al., iScience 2020). Heterogeneity of tumor tissue organization and stromal cell interactions was reported by single-cell analysis (Lotsberg et al., Front Oncol 2022). 

Krakstad group: The Bergen Gynecologic Cancer Research Group

The group has focused on studies of various classes of biomarkers in gynecologic tumors, in particular endometrial and cervical cancer, combining basic and translational studies. PDX models and organoids have been established. Results on single-cell analysis have indicated low epithelial vimentin expression as a marker of recurrent disease in low-stage endometrial cancer (Lien et al., eBioMedicine 2023). Studies of mismatch repair markers, in particular MSH6, and prognosis were reported (Berg et al., Br J Cancer 2022), in addition to the biomarker value of HER2 expression in endometrial cancer (Halle et al., Br J Cancer 2018; Krakstad et al., JAMA Oncol 2024). 

Lorens group: The Tumor Plasticity Group 

The group has focused on the Axl receptor and in particular its role in tumor cell plasticity and immune regulation in malignant tumors. It was reported that Axl is a driver of stemness in normal mammary gland and breast cancer (Engelsen et al., iScience 2020). The group also found that Axl targeting overcomes human lung cancer cell resistance to NK and CTL-mediated cytotoxicity (Terry et al., Cancer Immunol Res 2019), and that small-molecule inhibition of Axl targets tumor immune suppression and enhances chemotherapy effects in pancreatic cancer (Ludwig et al., Cancer Res 2018). Lorens is a co-founder of BerGenBio ASA and has facilitated interactions with the company. 

Strell group: The Early Breast Cancer Group

The focus of the group has been to study characteristics of early breast cancers, including non-invasive tumors like DCIS, by using advanced and integrated spatial mapping of genetic and proteomic alterations. Moreover, the aim is also to develop clinically relevant treatment stratification models for women with early-stage breast cancer. The importance of immune response patterns for the progress of DCIS was reported (Schiza et al., Eur J Cancer 2022), and the group found that high PDGFRb expression predicts resistance to radiotherapy in DCIS (Strell et al., Clin Cancer Res 2021). Recently, the use of beta-blockers was found to protect patients with DCIS from tumor recurrence (Strell et al., BCRT 2024).

Wik group: Breast Cancer of the Young – Bergen (BCY-B) 

The group has focused on molecular and clinico-pathologic differences between breast cancers among young patients compared to the older group, and how findings can eventually be relevant for therapy stratification. Results have been presented on increased proliferation in breast cancer of the young, and on a proliferation related gene signature focusing on age differences (Ingebriktsen et al., Br J Cancer 2022; Svanøe et al., Int J Cancer 2024). Also, the presence of age-related immune phenotypes has been reported (Ingebriktsen et al., Mod Pathol 2024).

Bjørge group: The INOvA Group

The group has focused on experimental and clinical approaches to advance the treatment of aggressive high-grade ovarian cancer based on molecular profiling, partly in collaboration with the Mc Cormack group. Reports on novel immune profiling of the tumor microenvironment of high-grade ovarian cancer have been presented (Anandan et al., Cancers 2021; Torkildsen et al., Front Immunol 2024). Also, the group reported that CD24-based intra-operative imaging might improve experimental surgical treatment of ovarian cancer
(Kleinmanns et al., eBioMedicine 2020).

Gjertsen group: Signaling-Targeted Therapy Group

The focus of the group has been to apply single-cell immune and signaling profiling for early response evaluation of myeloid leukemia patients, as well as therapy development using single-cell analysis as companion diagnostics. The use of early single-cell signaling profiling for response prediction, as a functional biomarker, was reported for AML patients, paving the way for adaptive treatment (Tislevoll et al., Nat Commun 2023). Single-cell analysis of CML patients have also been presented for a trial setting (Gullaksen et al., Haematologica 2017). The use of multiplexed antibodies for improved in vivo imaging of AML cell xenografts was described (McCormack et al., Blood 2013).

Straume group: The Tumor Biology and Clinical Trials Group

The group has focused on predictive biomarkers in clinical materials and trials, with reference to processes like angiogenesis, tumor immune responses, tumor cell plasticity, and escape from tumor dormancy (i.e. late relapses). Related to dormancy and late recurrences, the team reported that the recurrence pattern following breast reconstruction after mastectomy for breast cancer suggests a promoting effect of surgery on escape from tumor dormancy (Dillekås et al., BCRT 2016). In a trial of metastatic melanoma treated with bevacizumab monotherapy, liquid biopsies for ctDNA indicate changes in tumor load following therapy (Forthun et al., Sci Rep 2019). From the same trial, the group reported that expression of β2-adrenergic receptor in tumor tissue from patients was associated with clinical benefit (Schuster et al., Cancer Med 2023). Indications of a new relationship between FOXP3 and response to immunotherapy in advanced melanoma have been observed (ESMO 2023; meeting abstract).

Cairns group: The Health Economics Group

The group has focused on health economics in CCBIO and started with a dual focus: on the economic evaluation of cancer biomarkers, and on understanding the incentives to combine biomarkers with patented medicines. The team has published several papers on biomarkers and cost-effectiveness of cancer therapy. It was reported that in general, cancer patients have benefited from biomarker testing (D′Avó Luis & Seo, Eur J Health Econ 2021). Papers on the use of RWD (real world data) on processes of drug appraisals have been presented (Kang & Cairns, BMJ Open 2024). In colorectal cancers, biomarkers were mostly found to be cost-effective (Seo & Cairns, PLoS One 2018). In 2021, Seo & Strong presented guidelines for conducting biomarker cost-effectiveness assessments (Seo & Strong,
PharmacoEconomics 2021).

Norheim group: The Bergen Centre for Ethics and Priority Setting in Health (BCEPS)

The group’s aim has been to explore and promote ethically acceptable, fair and efficient priority setting in health. The main research questions relate to how cancer biomarkers can inform and improve health care priority setting. The team reported how concerns for efficiency and fair distribution of health can be implemented into drug appraisals and reimbursement decisions (Tranvåg et al., JAMA Netw Open 2022). The use of biomarkers in priority setting has been presented, alongside patient characteristics like age, physical function and comorbidity. (Tranvåg et al., BMC Med Ethics 2021), and the importance of patients’ age in these decisions has been reported on (Tranvåg et al., BMC Cancer 2018).

Strand group: Ethical, Legal and Societal Aspects (ELSA) Group

The group has focused on ethical, legal and societal aspects (ELSA) of CCBIO’s research, concentrating on improved self-reflection and increased RRI awareness (i.e. responsible research and innovation). This has been mirrored by continuous efforts in research and education, in general as well as directed towards specific topics and PhD projects. The team is responsible for the CCBIO903 course on Cancer research: Ethical, economic and social aspects. A major output is the book published in 2022 by Springer: Bremer A & Strand R (eds) (2022). Precision Oncology and Cancer Biomarkers: Issues at Stake and Matters of Concern.

Jonassen group: Translational Bioinformatics Group

The group has developed algorithms and tools for analysis of molecular information including gene expression and single-cell data (CyToF, Imaging Mass Cytometry). A novel computational method of deconvoluting expression data to account for tissue heterogeneity and distribution of cell types was reported (Dimitrakopoulou et al., BMC Bioinformatics 2018). The group presented novel ways to utilize machine learning and systems biology modeling to help predict treatment response of individual patients (Tislevoll et al., Nat Commun 2023). Also, the group developed new methods for spatial analysis by imaging mass cytometry using graph-based representation of tissue images (Ehsani et al., Bioinform Adv 2023).