FRIMEDBIO-Fri prosj.st. med.,helse,biol

Metastasis accounts for >90% of cancer-related mortality. Malignant cells carry oncogenic mutations that engender uncontrolled growth and epigenetic activation of stem cell features, chemotherapeutic resistance, immune modulation and metastasis. Tumor cel l epithelial-to-mesenchymal transition (EMT) is an embryonic gene program that is inappropriately evoked by microenviromental factors is strongly associated with tumour-initiating, drug resistant, cancer stem cells, progression to metastasis and poor prog nosis. We reported in PNAS earlier this year that the receptor tyrosine kinase, Axl, is essential for breast cancer metastasis. Axl expression in patient breast cancers, strongly correlated with poor overall survival and was elevated in matched metastases . Axl is strongly upregulated in breast carcinomas by EMT induction, via a novel vimentin-dependent mechanism. Axl-activation is necessary for sustained EMT transcription factor expression, and to maintain breast cancer stem cell functions including self- renewal, invasiveness and resistance to chemotherapeutics. Importantly, Axl is expressed in mammary stem cells and likely plays a role in regulating normal stem cell functions. This supports the hypothesis that Axl expression demarcates the acquisition of cancer stem cell features during breast cancer development that drives metastasis and therapeutic resistance. We propose a model where autocrine Axl signaling sustains the cancer stem cell phenotype via a mesenchymal positive feedback loop. We propose to delineate Axl-dependent molecular mechanisms that regulate normal mammary and malignant stem cell functions, using combined genetic and chemical probe screening and signal transduction pathway analysis in in vitro breast cancer stem cell models, organoty pic human mammary cell systems and experimental in vivo breast cancer models. Hence, inhibiting Axl signaling may target mammary cancer stem cells and provide an innovative basis for breast cancer treatment.