Editors' ChoiceCancer

Protumorigenic switches in TGF-β signaling

Sci. Signal.  15 Mar 2016:
Vol. 9, Issue 419, pp. ec60
DOI: 10.1126/scisignal.aaf6696

Signaling by transforming growth factor–β (TGF-β) has diverse outputs (see the Review by Akhurst and Padgett). In research published in Science Signaling, Budi et al. found that fibroblasts and epithelial cells responded to insulin—a hormone necessary for glucose metabolism and commonly used to treat diabetes—by transporting TGF-β receptors from intracellular stores to the plasma membrane. More receptors on the cell surface meant a greater response to TGF-β, including induction of epithelial-mesenchymal transition (EMT), a process that is associated with fibrosis and metastasis. The findings may explain why diabetics receiving insulin therapy have increased incidence of fibrosis, how metabolic syndrome associated with increased insulin in the circulation increases cancer risk, and how TGF-β signaling contributes to the progression of tumors.

Various complexes of the transcription factor family of SMADs mediate TGF-β–induced gene expression. Mutations that inactivate SMAD4, a SMAD that forms complexes with other SMAD proteins to enable transcriptional regulation, are common in patients with pancreatic ductal adenocarcinoma (PDAC), which involves an inflammatory progression and recruitment of TGF-β–secreting cells into the tumor microenvironment. David et al. found that this loss of SMAD4 in pancreatic cells enabled a protumorigenic switch in the transcriptional landscape triggered by TGF-β. In mice expressing mutant Kras but wild-type Smad4 in the pancreas, the incidence of PDAC was lower and the rate of apoptosis in pancreas cells was higher than those in mice lacking Smad4 with mutant Kras in the pancreas. Cells in SMAD4 wild-type, but not deficient, pancreata exhibited EMT, and time-lapse imaging indicated that EMT preceded apoptosis. The presence of SMAD4 in SMAD2 or SMAD3 complexes induced the expression of the genes encoding the transcription factors SNAIL and SOX4 in response to TGF-β. Although typically associated with cell proliferation, in SMAD4 wild-type pancreatic cells, SOX4 bound and promoted the expression of apoptotic genes Bim and Bmf. The expression of Sox4 was also induced by TGF-β in Smad4-deficient cells, as was that of the gene encoding an endodermal lineage transcription factor KLF5. In contrast, TGF-β mediated SNAIL-dependent repression of Klf5 in SMAD4 wild-type cells. Many of the loci bound by SOX4 overlapped with those bound by KLF5, and knocking down KLF5 increased apoptosis and inhibited growth in tumors. Therefore, the loss of SMAD4 (and hence SNAIL) in PDAC promotes a protumorigenic switch in the TGF-β response. The authors propose that KLF5 directs the activity of SOX4 to progenitor proliferation genes rather than apoptotic genes. These studies show how changes in the molecular composition within the cell (which transcriptional regulators are present) and in its environment (the presence of growth factors) can markedly alter the cell’s ultimate response to the same signal.

C. J. David, Y.-H. Huang, M. Chen, J. Su, Y. Zou, N. Bardeesy, C. A. Iacobuzio-Donahue, J. Massagué, TGF-β tumor suppression through a lethal EMT. Cell 164, 1015–1030 (2016). [PubMed]

R. J. Akhurst, R. W. Padgett, Matters of context guide future research in TGFβ superfamily signaling. Sci. Signal. 8, re10 (2015). [Abstract]

E. H. Budi, B.-P. Muthusamy, R. Derynck, The insulin response integrates increased TGF-β signaling through Akt-induced enhancement of cell surface delivery of TGF-β receptors. Sci. Signal. 8, ra96 (2015). [Abstract]