The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis. We here report that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers. Furthermore, we show that those cells have an increased ability to form mammospheres, a property associated with mammary epithelial stem cells. Independent of this, stem cell-like cells isolated from HMLE cultures form mammospheres and express markers similar to those of HMLEs that have undergone an EMT. Moreover, stem-like cells isolated either from mouse or human mammary glands or mammary carcinomas express EMT markers. Finally, transformed human mammary epithelial cells that have undergone an EMT form mammospheres, soft agar colonies, and tumors more efficiently. These findings illustrate a direct link between the EMT and the gain of epithelial stem cell properties.

Approach Summary Licensing status Publication and contact information Drug platforms Chemically mediated somatic cell reprogramming Cell-culture studies suggest that inhibitors of chromatin-modifying enzymes can increase the efficiency with which somatic cells are reprogrammed to pluripotent stem cells, providing a potential boon to the development of stem cell-based therapies. In mouse embryonic fibroblasts expressing four transcription factors (Oct4, Sox2, Klf4 and c-Myc) that are sufficient to induce pluripotency, small molecule inhibitors of DNA methyltransferase or histone deacetylase (HDAC) significantly increased reprogramming efficiency compared with that seen in dimethyl sulfoxide (DMSO)-treated controls (p<0.05). The HDAC inhibitor valproic acid (VPA) showed the strongest effect, with an increase of over 100-fold in programming efficiency compared with that seen in DMSO-treated controls (p<0.001). Next steps include assessing VPA's effects in human somatic cells and conducting a high throughput screen of small molecule libraries to identify other candidates for chemical-based cellular reprogramming. Patent pending for VPA effects on reprogramming; available for licensing through Harvard

During progression from tumour growth to metastasis, specific integrin signals enable cancer cells to detach from neighbouring cells, re-orientate their polarity during migration, and survive and proliferate in foreign microenvironments. There is increasing evidence that certain integrins associate with receptor tyrosine kinases (RTKs) to activate signalling pathways that are necessary for tumour invasion and metastasis. The effect of these integrins might be especially important in cancer cells that have activating mutations, or amplifications, of the genes that encode these RTKs.