BBB Seminar: James Lorens
Stem cells, EMT and cancer: The role of the Axl receptor
Department of Biomedicine, University of Bergen
Epithelial cell plasticity allows conversion between phenotypic states that provide a broad repertoire of cellular functions necessary during embryonic development and organogenesis. Homeostasis of adult epithelia requires a pool of stem/progenitor cells that utilize the epithelial-to-mesenchymal transition (EMT) gene program to maintain stem and multipotent progenitor phenotypes. Neoplastic epithelial cells can activate EMT in response to gene mutations and microenvironmental effectors such as hypoxia, inflammation and chemotherapy. The EMT gene program endows carcinoma cells with the phenotypic plasticity characteristic of adult epithelial stem cells, facilitating metastasis and therapeutic resistance.
The Axl receptor tyrosine kinase is widely expressed in cancer and correlates with drug resistance, metastasis and poor patient survival. We demonstrate that induction of EMT activates Axl signaling that is required to maintain EMT-related invasive, survival and cancer stem cell (CSC) traits of malignant breast cancer cells. Targeting Axl signaling blocks the EMT/CSC gene program and inhibits malignant functions including invasiveness, drug resistance, mammosphere formation, in vivo tumor initiation, and spontaneous metastasis in orthotopic breast cancer models. These results illustrate that Axl receptor function is requisite for the maintenance of cancer stem cell-like traits during malignant progression.
In spite of this prevalence in cancer, the reported normal functions of Axl do not explain its contribution to malignancy. We hypothesized that Axl may play an unappreciated role in the normal mammary epithelial hierarchy. Congruently, we show that Axl is expressed on rare subrabasal human breast epithelial stem/progenitor cells. Axl-expressing mammary epithelial cells represent a distinct subset of progenitors with multipotent capacity that is dependent on Axl signal transduction. Hence, Axl receptor represents a new mechanistic connection between normal stem cell regulation, EMT and the cancer stem cell phenotype. Clinical Axl inhibitors thus represent a novel therapeutic avenue to target EMT/CSC traits of aggressive cancer.
Chair: Rolf K. Reed, Department of Biomedicine