Editors' ChoiceCancer

Two faces of WNT signaling

Sci. Signal.  19 Apr 2016:
Vol. 9, Issue 424, pp. ec89
DOI: 10.1126/scisignal.aaf8916

A pair of papers this week show that endogenous production of natural inhibitors of the WNT/β-catenin pathway has opposite effects in the childhood cancer medulloblastoma and in melanoma, a cancer most common in older adults. Medulloblastoma is a brain cancer classified into subtypes on the basis of mutations and the site of origin in the brain. Whereas those associated with mutations that activate the Sonic hedgehog (SHH) pathway tend to be most aggressive, less responsive to chemotherapy, and often fatal; those with activating mutations in β-catenin tend to be curable. Phoenix et al. identified differences in the penetrability of the blood brain barrier as responsible. WNT-type medulloblastoma secreted the WNT inhibitors WIF1 and DKK1, which functioned as a paracrine inhibitory signal in tumor-associated endothelial cells and disrupted their barrier function. In contrast, few cells of the SHH-type medulloblastoma had detectable WNT/β-catenin activity, and most of the associated endothelial cells had active WNT/β-catenin signaling and formed a functional barrier. These distinct properties affected the penetrance of peripherally delivered chemotherapeutic drugs, such that, although both types of cancer cells were killed in culture by the drugs, only the WNT-type medulloblastoma was affected when implanted into mouse brains. Injecting WNT-type medulloblastoma cells that produced WNT7A stabilized the barrier function of the endothelial cells and rendered these tumors resistant to chemotherapy. Thus, combining WNT inhibitor with chemotherapy, or pretreating with a WNT inhibitor, to improve delivery of the drugs into the tumor may be beneficial in treating more aggressive forms of medulloblastoma.

In the second paper, Kaur et al. examined how the age of dermal fibroblasts affected melanoma progression and reported that aged fibroblasts produced the WNT antagonist secreted frizzled-related protein 2 (sFRP2). In melanoma, β-catenin activity promotes proliferation but inhibits invasiveness of the tumor cells. Given that metastasis is the cause of lethality, keeping the cells in a proliferative, noninvasive state may be beneficial. Melanoma cells injected into young or old mice and cultured in organotypic skin reconstructions with fibroblasts from old (>55) or young (<35) human donors exhibited increased proliferation in the young condition and increased invasiveness (in culture) or metastasis (in the mice) in the old condition. Conditioned medium from the aged fibroblasts, which contained sFRP2, or conditioned medium from young fibroblasts supplemented with sFRP2 inhibited proliferation and increased invasiveness of melanoma cells in culture; a similar effect of increased metastasis occurred in the melanoma mouse model when the young mice received sFRP2. Melanoma cells exposed to aged fibroblast conditioned medium or grown in aged mice had reduced abundance of β-catenin, the transcription factor MITF, and APE1 (encoded by a MITF target gene), compared with those in melanoma cells grown in young conditions. Because APE1 is a multifunctional protein involved in DNA damage repair and responding to reactive oxygen species (ROS), unsurprisingly the melanoma cells grown in aged conditions exhibited a gene signature associated with the DNA damage response and an increase in the amount of a marker of oxidative stress, compared with those grown in the young condition. These results are particularly intriguing, because increased ROS and decreased β-catenin and MITF are associated with resistance to BRAF inhibitors, a major therapeutic strategy used to treat melanoma. Treating melanoma cells with conditioned medium from young fibroblasts that had been exposed to H2O2 resulted in resistance to the BRAF inhibitor vemurafenib; whereas treating melanoma cells with conditioned medium from aged fibroblasts that had been exposed to the antioxidant NAC even without adding vemurafenib caused cell death. These data suggest that the age-dependent increase in sFRP2 reduces WNT signaling and adapts the cells to high ROS, thus antioxidant therapy may be particularly beneficial in treating melanoma in patients over a certain age that exhibit high amounts of sFRP2.

T. N. Phoenix, D. M. Patmore, S. Boop, N. Boulos, M. O. Jacus, Y. T. Patel, M. F. Roussel, D. Finkelstein, L. Goumnerova, S. Perreault, E. Wadhwa, Y.-J. Cho, C. F. Stewart, R. J. Gilbertson, Medulloblastoma genotype dictates blood brain barrier phenotype. Cancer Cell 29, 508–522 (2016). [PubMed]

A. Kaur, M. R. Webster, K. Marchbank, R. Behera, A. Ndoye, C. H. Kugel III, V. M. Dang, J. Appleton, M. P. O’Connell, P. Cheng, A. A. Valiga, R. Morissette, N. B. McDonnell, L. Ferrucci, A. V. Kossenkov, K. Meeth, H.-Y. Tang, X. Yin, W. H. Wood III, E. Lehrmann, K. G. Becker, K. T. Flaherty, D. T. Frederick, J. A. Wargo, Z. A. Cooper, M. T. Tetzlaff, C. Hudgens, K. M. Aird, R. Zhang, X. Xu, Q. Liu, E. Bartlett, G. Karakousis, Z. Eroglu, R. S. Lo, M. Chan, A. M. Menzies, G. V. Long, D. B. Johnson, J. Sosman, B. Schilling, D. Schadendorf, D. W. Speicher, M. Bosenberg, A. Ribas, A. T. Weeraratna, sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532, 250–254 (2016). [PubMed]