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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.



If you have supported the release of political prisoners in Catalonia (through donation or purchase at the ANC or Omnium) please send me an email and I will send you a free photography from the catalog (go to Miscellany > Pictures).

Si has donat suport a l'alliberament dels presos polítics Catalans (a través de donació o compra a l'ANC o Omnium) envieu-me un correu electrònic i us faré arribar la fotografia que desitgeu del catàleg (aneu a Miscellany > Pictures).


Selected publications

2017. Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. Oncogene 36(19):2737-2749.

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.