Mechanisms of Tumor Cell Plasticity
The aim of Professor Lorens´ team is to understand the molecular mechanisms of acquired drug resistance.
Tumors are remarkably heterogeneous, the result of selective forces acting on genetically unstable tumor cells during cancer development and progression. Phenotypic plasticity, a feature of cancer spread and treatment resistance, endows tumor cells with astonishing functional flexibility that allows adaptation to different niches within the dynamic tumor microenvironment.
- Study of the role of the Axl receptor tyrosine kinase in the phenotypic plasticity of adult epithelial stem cells. Results show that Axl signaling is coopted during breast tumorigenesis, providing a rationale for its widespread expression in cancer.
- Axl is broadly associated with malignancy, drug resistance and poor patient survival, and further associated with evasion of anti-tumor immunity. Axl regulates both tumor cell plasticity and anti-tumor innate immunity in the tumor microenvironment.
- The vitamin K-antagonist warfarin, a popular anti-coagulant in clinical use, has anti-tumor activity attributed to the disruption of vitamin K-dependent post-translational modification of the Axl ligand, Gas6. Warfarin inhibits malignant traits and enhances antitumor immune responses. The group investigated the association between the warfarin use and cancer incidence in a large Norwegian population cohort. The results revealed a remarkable reduction in cancer incidence associated with warfarin use across tumor types.
In Ludvig, et al. (2017) the group showed in collaboration with Rolf Brekken (Dallas) that Axl kinase inhibition blocked the aggressive traits of pancreatic cancer cells and enhanced the efficacy of gemcitabine in patientderived xenografts and late-stage murine models by targeting the tumorimmune interface. Axl inhibition drove tumor cell differentiation and reversed gemcitabine resistance mechanisms, and potentiated an immune stimulatory microenvironment by targeting immune suppressive myeloid cell types.
In Haaland et al. (2017) the group reported that use of the anticoagulant warfarin was associated with a lower risk of new cancers in people over 50 years. This population-based cohort study using Norwegian national registry data comprised 1.25 million Norwegians. In the subgroup of people using warfarin for atrial fibrillation or atrial flutter, cancer risk was lower at any site and in all four common sites (lung, prostate, breast, and colon). Warfarin, used by millions of adults worldwide, may be associated with lower cancer incidence across a broad range of malignant neoplasms.
The group has established state-ofthe-art mass cytometry methodology to allow high dimensional measurement of phenotypic variation in the tumor microenvironment. They are studying how vitamin K-dependent post-translational modifications of Gas6 regulate Axl cell signaling, how Axl signaling supports phenotypic plasticity reprogramming and how this affects tumor-immune cell interactions. Based on mechanistic insights, the group will evaluate new biomarkers and immunotherapeutic combinations based on Axl targeting.
Current challenges in the field
In spite of the significant advances in new anti-cancer treatments that provide significant clinical responses, most patients still do not achieve long-lasting clinical benefit. Cancer cells invariably elude treatment through acquired drug resistance, reemerging as advanced, disseminated malignancy that is associated with increased mortality.
2016 Spring Interview
In 2015, James Lorens won the Helse Vest Innovation Prize for his work with developing first-in-class drugs for aggressive, immune-evasive, drugresistant and metastatic cancers. His research has resulted in the company BerGenBio, committed to discovering and developing novel drugs for treating cancer patients.
You work with the mechanisms of tumor cell plasticity. Can you explain what it is and why it is relevant?
"Cellular plasticity describes the ability of cells to change their state. Well studied examples include stem cell differentiation, transdifferentiation, and more recently experimentally induced pluripotent stem cells. Common to these is an epigenetic reprogramming that alters gene expression of hundreds or thousands of genes. Normal cellular plasticity programs are strongly dependent on microenvironmental cues (“niches”). Tumor cells can activate these plasticity programs through interplay between mutations in their genomes and interactions with the tumor microenvironment. This endows tumor cells with enhanced adaptive abilities and new cellular functions that underlie tumor heterogeneity, metastasis and drug resistance. Understanding this is crucial to inform better cancer treatment options."
Are you targeting certain cancer types in your research?
"Most, if not all, cancer types can undergo some form of cellular plasticity under specific conditions. Hence we study this phenomenon in several cancer cell types, including breast, lung and skin cancers."
What is the most important thing that you have learned?
"We have uncovered a novel link between how the Axl receptor tyrosine kinase influences tumor plasticity and how it regulates normal stem cells. This provides a rationale for the wide spread association of Axl with aggressive cancers."
How do you see your findings benefiting future cancer patients?
"The Axl receptor is a target of new therapeutics in clinical trials. Our insights can thus be readily translated to address tumor plasticity that contributes to current treatment failures."
See Lorens' PubMed publication list here.