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.
This phenotypic plasticity also allows adaptation of tumor cells to microenvironmental challenges such as hypoxia, inflammation and drug treatment that facilitate malignant progression, metastasis and drug resistance. Gene expression programs related to the epithelial-to-mesenchymal transition (EMT) are utilized both by normal and neoplastic epithelial cells to access stem cell-related functions.
Using comparative functional approaches, the team is investigating the relationship between regulators of EMT in tumor cells in maintenance of normal stem and progenitor cells. Recent results highlight the Axl receptor tyrosine kinase as a key regulator of both normal adult epithelial stem- or progenitor cells and a determinant of carcinoma cell plasticity. These studies on Axl signaling have provided new insights into the regulation of tumor phenotypic heterogeneity and formed a basis for the recent clinical translation of novel Axl inhibitors. Further studies are ongoing on how distinct combinations of microenvironmental factors regulate phenotypic plasticity in normal and cancer cells using a new screening technology.
Using these mechanistic insights Lorens and his team are exploring how microenvironmental factors regulate tumor cell plasticity underlying contextual drug responses.
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.