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How cancer cells adapt to mTOR inhibition?

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition

Oncogene (2016), 1–13.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.


Open positions (pre and postdoctoral)

The Catalan Institute of Oncology (ICO) is a public center working exclusively in the field of cancer. Its approach to the disease is comprehensive, combining, all in one organization, prevention, care, specialized training and research. The ICO was founded in 1996 and has become a center of reference in Catalonia, both in healthcare quality and in research (top Spanish hospital-institute in terms of scientific impact). The Pujana's research group is part of the newly created ICO ProCURE research program, aimed at addressing a major clinical problem in oncology; the existence or emergence of cancer therapeutic resistance. The group is located in the Bellvitge Institute for Biomedical Research (IDIBELL) campus.

grup 2016 2

Selected publications

2016. Cancer network activity associated with therapeutic response and synergism. Genome Medicine 24;8(1):88.

2015. Integrating germline and somatic data towards a personalized cancer medicine. Trends Molecular Medicine 20(8):413-5.

2011. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. PLoS Biology Nov;9(11):e1001199.

2010. Biological reprogramming in acquired resistance to endocrine treatment of breast cancer. Oncogene 29(45):6071-83.

2007. Network modeling links breast cancer susceptibility and centrosome dysfunction. Nature Genetics 39(11):1338-49.