Mechanisms of Tumor Cell Plasticity
The aim of Professor Lorens´ team is to understand the molecular mechanisms of acquired drug resistance.
In spite of significant improvement in cancer therapy, most cancer patients will not experience lasting benefit. Understanding why therapies fail and developing novel biomarkers and treatment paradigms to address these resistance mechanisms remains a central goal for cancer research. The group discovered that the receptor tyrosine kinase AXL is a key driver of acquired resistance to multiple cancer agents. By determining the molecular mechanism of AXL regulation of the tumor microenvironment, in concert with combination clinical trials with AXL targeting agents, a new paradigm to improve cancer treatment has emerged.
Subprojects and important results
1. AXL is a Key Factor for Cell Plasticity and Promotes Metastasis in Pancreatic Cancer
Single-cell RNA-sequencing revealed that AXL is highly expressed in tumor cells that have EMT. AXL deficiency extended survival, reduced primary and metastatic burden, and enhanced sensitivity to gemcitabine in murine models of pancreatic ductal adenocarcinoma (PDA). PDA in AXL-deficient mice displayed a more differentiated histology, higher nucleoside transporter expression, and a more active immune microenvironment compared with PDA in wild-type mice. Finally, the group demonstrated that AXL-positive poorly differentiated tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target in PDA.
2. AXL in renal carcinoma
High AXL-expression level in tumor cells was associated with lower response rates and a trend to shorter progression-free survival following anti-PD-1 treatment in clear-cell renal cell carcinoma (ccRCC). AXL expression was strongly associated with tumor-PD-L1 expression, especially in tumors with VHL inactivation. Moreover, patients with tumors displaying concomitant PD-L1 expression and high AXL expression had the worst overall survival. In orthotopic ccRCC murine models, AXL targeting with small molecule kinase inhibitor or function-blocking antibody inhibited tumor progression. These findings propose AXL as a candidate therapeutic target in advanced ccRCC.
Deeper understanding of the role of the tumor microenvironment (TME) during cancer initiation and progression is critical both to further cancer biology and as a source of improved molecular diagnostics and therapeutics.
The group will focus on determining how AXL receptor signaling regulates acquired resistance to cancer therapy. The unique signal transduction of GAS6–AXL complexes will be studied using systems-level signal transduction analysis and high dimensional singlecell mapping of phenotypic-spatial features of the tumor microenvironment in preclinical models and cancer patient biopsy samples.
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.