Mechanisms of Tumor Cell Plasticity
Professor Lorens´ team is working on how epithelial cell plasticity between epithelial and mesenchymal phenotypic states provides a repertoire of cellular functions required during embryonic development, organogenesis and adult tissue repair and homeostasis.
About the group and its research focus
The major challenge for current cancer treatments is the remarkable heterogeneity of tumors. This is the result of selective forces acting on evolving and genetically unstable tumor cells during cancer progression. The breakdown of normal tissue structure exposes tumor cells to numerous biophysical challenges, nutritional deprivation and a hostile non-native microenvironment comprising different matrix proteins and a variety of stromal and immune cells. In response, tumor cells trigger cellular plasticity reprogramming characteristic of adult tissue homeostasis and repair. This endows tumor cells with astonishing functional flexibility that allows adaptation to different niches within the dynamic tumor microenvironment. This “hallmark” of cancer, tumor cell plasticity, is a central feature of cancer spread and treatment failure.
The group’s research focuses on understanding the molecular mechanisms that endow tumor cells with adaptive cellular plasticity in the context of acquired drug resistance. The goal is to determine new avenues of therapeutic intervention to improve our ability to treat aggressive cancers.
The group’s recent results highlight how carcinoma cells coopt cellular plasticity programs that normally regulate adult tissue responses to injury, to achieve resistance to current anti-cancer therapies. They discovered that the Axl receptor tyrosine kinase is a common regulator of both normal adult epithelial stem cells and aggressive carcinoma cells. Cancer cells utilize Axl signaling to support phenotypic plasticity, activate cell survival mechanisms and achieve resistance to anti-cancer therapies. The group’s studies on Axl provide new insight into the how tumors become more heterogeneous in response to microenvironmental factors and effector immune cell challenge.
In particular, the results reveal an unexpected commonality between acquired resistance to chemo-, targeted and immunotherapeutic agents that is related to Axl activity.
The Axl receptor is effectively targeted by the clinical stage small molecule kinase inhibitor BGB324. The group’s studies demonstrate that selective Axl inhibition improves the efficacy of different cancer therapeutics in several preclinical models. Clinical translation of these results is ongoing in current Phase I/II clinical trials in acute myeloid leukemia and non-small cell lung cancer. The first results from these trials are encouraging and further trials are planned.
Lie et al., Inhibition of Axl in erlotinibresistant NSCLC cells abrogates autophagic flux and induces immunogenic cell death. Poster presentations at the 28th EORTC-NCI-AACR Symposium (Munich), 2016 CCBIO Symposium (Bergen); manuscript in preparation. First description of a novel Axl-dependent cell survival mechanism underpinning cross-resistance to multiple anti-cancer treatments. This project is the foundation for an RCN Mobility Grant to CCBIO Postdoc Agnete Engelsen to work with CCBIO Associate Professor J.P. Thiery at the Gustave Roussy in Paris.
Terry et al., Hypoxia-induced EMT drives non-small cell lung cancer cell phenotypic plasticity and immune resistance oncoimmunology, in press. First report of Axl-dependent cancer cell resistance to NK-mediated cytotoxicity. Collaboration with Professor S. Chouaib and with CCBIO Associate Professor J.P. Thiery at the Gustave Roussy in Paris.
Ertsås et al., Microsphere cytometry to interrogate microenvironment-dependent cell signaling. Integrative Biology, in press. This describes new flow cytometry-based technology to study microenvironment-dependent cell signaling. Collaboration with CCBIO Associate Professor M. LaBarge (LNBL and City of Hope) and Professor Garry Nolan (Stanford).
Plans for the future
The group is exploring the role of Axl signaling in resistance to the new class of cancer immunotherapies (immune checkpoint inhibitors). Their results show that Axl inhibition sensitizes cancer cells to the anti-tumor immune response and can be used to improve immune checkpoint inhibitor efficacy. In collaboration with leading international cancer researchers they are studying the mechanistic basis for this observation. They hope to shed new insight into how cancer cells interact with the immune system that can be used to improve cancer immunotherapy.
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.