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

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

Proteaceae Leaf Fossils: Phylogeny, Diversity, Ecology and Austral Distributions

Foliar fossils of Proteaceae are reviewed, and useful specimens for interpreting evolution, and past and present distributions and environments are discussed. There are no definite Cretaceous occurrences. However, there is evidence of extant lineages dating from the Paleocene onwards, including tribe Persoonieae of subfamily Persoonioideae and each of the four tribes of subfamily Grevilleoideae. High diversity and abundance characterizes the Australian fossil record, including sclerophyllous and xeromorphic forms, but there is little evidence of the prominent extant subfamily Proteoideae. New Zealand had a much higher diversity of Proteaceae than at present, including Oligo-Miocene species of open vegetation. The South American leaf fossil record is not extensive. However, the fossil records of Embothrieae and Orites are consistent with the distributions of their extant relatives in South America and Australia being the result of vicariance. Overall, there is a need for more research on placing Proteaceae leaf fossils in a phylogenetic context.Raymond J. Carpente