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Centre for Cancer Biomarkers CCBIO

Mechanisms of Tumor Cell Plasticity

The aim of Professor Lorens´ team is to understand the molecular mechanisms of acquired drug resistance.

Portrait photo.
Photo:
Ingvild Festervoll Melien

Research focus

The Lorens group discovered that the AXL receptor tyrosine kinase is an essential regulator of tumor EMT, of acquired drug resistance, and of the anti-tumor immune response. Although seldom mutated, AXL expression in tumors is a universal poor prognostic factor for patient outcomes. AXL is also a critical negative regulator of innate immune cell responses and is expressed by suppressive myeloid and tolerogenic dendritic cells in the tumors. The group’s recent results are translated phase II clinical trials.

Most cancer patients will not experience lasting benefits from current therapies. The Lorens group discovered that AXL is a key driver of acquired drug resistance. By uncovering the molecular mechanism of AXL regulation of the tumor micro-environment, in concert with combination clinical trials with AXL targeting agents, a new paradigm to improve cancer treatment has emerged.

Projects and important results

Current projects:

AXL in tumor-immune crosstalk
Tumor suppressive myeloid cells are a primary obstacle to immunotherapy. The Lorens group’s recent results show that AXL inhibition improves immune checkpoint inhibitor efficacy by blocking both tumor EMT and immune suppressive cell mechanisms. High dimensional mass cytometry demonstrated that AXLexpressing tumor suppressive myeloid cells were targeted by bemcentinib treatment. The group’s findings indicate that AXL signaling integrates cancer cell plasticity with immune suppressive myeloid and regulatory dendritic cell mobilization and that tumor immunity can be enhanced by combined ICB and AXL targeting.

AXL in acquired cancer therapy resistance
The group’s recent studies demonstrate that AXL signaling allows tumor cells to resist cytotoxic T-lymphocyte (CTL)-mediated cell killing by abrogating immune synapse formation, a prerequisite for the success of immunotherapeutic approaches. AXL signaling abrogates NK/CTL-mediated killing by decreasing ICAM1 surface expression that destabilizes the immune synapse. AXL inhibition stabilizes NK/CTL conjugation. These results suggest that AXL targeting will optimize T-cell-mediated anti-tumor immune responses.

As acquired cancer therapy resistance evolves under selection pressure of immune surveillance, it is expected that mechanisms which promote drug resistance through cell survival and immune evasion will be favored. The group found that EGFRi resistance in lung cancer was mediated by upregulation of AXL. Mass cytometry revealed cell signaling heterogeneity is incompatible with a simple bypass signaling mechanism. AXL inhibition abrogated cytoprotective autophagic flux and induced immunogenic cell death in drug resistant NSCLC. AXL and autophagy gene signatures were correlated in a large cohort of human NSCLC. The group’s results show that AXL signaling supports a drug resistant persister cell phenotype through a novel autophagy dependent mechanism and reveals a unique immunogenic effect of AXL inhibition on drug resistant NSCLC cells.

Future plans

The Lorens group will focus on determining how AXL receptor signaling regulates tumor intrinsic resistance to immunotherapy. They hypothesize that GAS6–AXL complexes have unique signal transduction attributes that support pro-survival and cytotoxic T-cell resistant cell states. They address this through systems-level signal transduction analysis, and high dimensional single-cell mapping of phenotypic-spatial features of the tumor microenvironment in cancer patient biopsy samples from ongoing phase II clinical trials.

Current challenges in the field

Identifying biomarkers and therapeutic vulnerabilities in the tumor microenvironment that address resistance to current targeted and immunotherapies is a major focus in the field.

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."

PubMed Publications