Editors' ChoiceCancer

Cutting Off EMT at the Pass

Sci. Signal.  17 Sep 2013:
Vol. 6, Issue 293, pp. ec223
DOI: 10.1126/scisignal.2004728

The epithelial-to-mesenchymal transition (EMT), through which cells revert to having stemlike phenotypes, is critical to the progression of cancer from early-stage, localized tumors to invasive metastases. Two studies identified key signaling molecules that induce transcriptional programs that promote EMT in breast and brain cancers. Using human mammary epithelial cells (HMLE) that underwent spontaneous EMT [lines the authors call NAMECs (naturally arising mesenchymal cells)] or EMT induced by overexpression of the transcription factors Twist, Snail, or Slug, Tam et al. identified an array of kinase-encoding genes that were substantially more expressed in CD44-positive mesenchymal cells than in the parental line. These included BMPR2, EPHA2 and EPHB2, AXL, CDK6, and PRKCA, which encode bone morphogenetic protein receptor type II, ephrin receptor A2 and B2, the kinase AXL, cyclin-dependent kinase 6, and protein kinase C α (PKCα), respectively. Apoptotic rates in cell cultures and tumor regression in xenograft mouse models indicated that NAMECs and HMLE-Snail, -Slug, and -Twist cell lines were substantially more dependent on PKCα for survival than was the epithelial parental line. Furthermore, proteomic analysis of a large panel of breast cancer cell lines and targeted pharmacological inhibition in NAMECs and HMLE-Twist cells showed that the more mesenchymal-like cells had decreased EGFR abundance and depended less on EGFR for survival, whereas they had increased abundance of platelet-derived growth factor receptor (PDGFR; a kinase upstream of PKCα) and phospholipase C-γ 1 and 2 (PDGFR-to-PKCα transducers), and depended more on PDGFR for survival. Additionally, the composition of the transcription factor complex AP-1 was switched in mesenchymal-like lines, with FRA-1 (Fos-related antigen 1), a PKCα substrate, replacing c-Fos. FRA-1–deficient HMLE were unable to undergo induced EMT, and the expression of FOSL1 (which encodes FRA-1) and PDGFR correlated with the more aggressive, mesenchymal subtypes of human breast cancer tissue.

In a second study, Bhat et al. found that proneural and CD44-positive mesenchymal subtypes of glioblastoma (GBM) had distinct transcriptome, methylation, and cell-surface antigen profiles. However, mesenchymal GBM–derived spheroid cultures (GSCs) reverted to proneural profiles, supporting the paradigm that EMT is a transient, reversible process. Therefore Bhat et al. looked for EMT-promoting components in the GBM microenvironment by treating proneural GSCs with various cytokines and growth factors. Only tumor necrosis factor–α (TNF-α) stimulated an increase in the cell-surface abundance of CD44 and a switch to a mesenchymal transcriptome. Likewise, only TNF-α decreased DNA damage signaling and G2/M cell cycle arrest in response to ionizing radiation, a treatment that GBM often resists. The mesenchymal switch and radioresistance induced by TNF-α were prevented by overexpression of a nondegradable mutant of inhibitor of κB (IκB), and temporal assays showed that the phosphorylation of p65 (the active form of the transcription factor NF-κB) preceded the induction of mesenchymal-associated transcription factors, indicating that NF-κB promotes EMT and confers radioresistance in GBM. A mesenchymal profile, NF-κB activity, and poor response to radiation were correlated in GBM patients. Together, these studies have identified critical components in EMT signaling that may be therapeutically targeted to prevent metastatic progression in breast and brain cancer.

W. L. Tam, H. Lu, J. Buikhuisen, B. S. Soh, E. Lim, F. Reinhardt, Z. J. Wu, J. A. Krall, B. Bierie, W. Guo, X. Chen, X. S. Liu, M. Brown, B. Lim, R. A. Weinberg, Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell 24, 347–364 (2013). [PubMed]

K. P. L. Bhat, V. Balasubramaniyan, B. Vaillant, R. Ezhilarasan, K. Hummelink, F. Hollingsworth, K. Wani, L. Heathcock, J. D. James, L. D. Goodman, S. Conroy, L. Long, N. Lelic, S. Wang, J. Gumin, D. Raj, Y. Kodama, A. Raghunathan, A. Olar, K. Joshi, C. E. Pelloski, A. Heimberger, S. H. Kim, D. P. Cahill, G. Rao, W. F. A. Den Dunnen, H. W. G. M. Boddeke, H. S. Phillips, I. Nakano, F. F. Lang, H. Colman, E. P. Sulman, K. Aldape, Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell 24, 331–346 (2013). [PubMed]