Burnham Institute for Medical Research, La Jolla, California

A biologist is gratified to find reconciliation for a conflicted receptor.

When giving talks on the involvement of the Eph family of receptor tyrosine kinases in cancer, I sometimes include a slide of the two-faced Roman god, Janus, to signify the dichotomies of Eph function in cancer cells. Most proteins have a clear-cut function. Some 'moonlighting' proteins carry out two unrelated functions. It is, however, rare for a protein to toggle between opposing activities. The Eph receptors are proving to be such outliers.

High expression of Eph receptors has been correlated with a poor cancer prognosis, but so has Eph silencing. Accordingly, there is good evidence that the Eph receptors can promote as well as inhibit tumour development. In a reconciliation reminiscent of Hegelian synthesis, a recent paper begins to explain how the EphA2 receptor can both promote and inhibit cancer cells' migratory and invasive abilities.

EphA2 activation by ephrin ligands seems to be minimal in most types of cancer cell. Hui Miao and Bingcheng Wang of Case Western Reserve University in Cleveland, Ohio, and their co-workers have shown that the protein Akt — which can be powerfully cancer-promoting — hijacks EphA2 by phosphorylating one of its serine residues, enabling its pro-metastatic activities (H. Miao et al. Cancer Cell 16, 9–20; 2009).

Remarkably, binding by the ephrin-A1 ligand erases this phosphorylation and transforms EphA2 into an anti-invasive molecule.

These findings lead to the counterintuitive proposition that we should encourage rather than inhibit EphA2's ligand-dependent function. It will be interesting to see whether analogous switches convert other Eph receptors between malignant and benign phenotypes.

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Johns Hopkins University, Baltimore, Maryland

A geneticist wonders what it takes to prove causality.

In the post-genomic era, we are increasingly confronted by a torrent of variation data, originating from gene sequence, copy number and methylation patterns. To complicate matters further, I anticipate that a notable fraction of variation among individuals will be found to be relatively rare events. This would severely hamper our ability to implement statistical methods to associate variants with disease pathogenesis.

A recent paper by Carpten et al. (Nature 448, 439–445; 2007) highlights just how difficult solving this problem can be. The authors found a somatic missense mutation in AKT1 in a small number (2–6%) of breast, colon and ovarian cancers, and expended considerable effort establishing its link to tumour development. Experiments included solving the AKT1 protein's crystal structure; calculating the predicted effect of the missense change on the protein's conformation and binding abilities; gauging phosphorylation rates of the protein; identifying cellular localization; measuring transformational competency of the mutant versus wild-type allele; and checking the mutant protein's ability to induce cancer in a mouse model.

In light of recent efforts to understand the total mutational load in cancer (for some examples see F. Dahl et al. Proc. Natl Acad. Sci. USA 104, 9387–9392; 2007; C. Greenman et al. Nature 446, 153–158, 2007; T. Sjöblom et al. Science 314, 268–274; 2006), these data are both exciting and sobering, because the idea of performing such an exhaustive analysis on a large allelic series is not tenable. The challenge, therefore, is to solve this problem by developing functional assays that are physiologically relevant; amenable to at least medium throughput; and applicable to a range of mechanistic questions (not just neoplasia, for example).

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University of California, San Francisco, USA

To an epigeneticist, cancer is encrypted in genes and their packaging.

Early in my career I had the good fortune to study epigenetics in a lab focused on the molecular genetics of cancer. At the time, geneticists typically thought that in cancer, epigenetic changes — which affect regulation of the genome but not the genome's sequence — were epiphenomena less worthy of study.

This might have made the experience akin to being a Republican mayoral candidate in left-leaning San Francisco; instead it was positively transforming.

As my own research group took shape, I began to integrate genetic and epigenetic theories of malignant transformation. Now, hereditary human cancers and genetically engineered mice once held up as evidence for genetic models also provide evidence for epigenetic models, and we study the interactions of the two mechanisms.

In this light, a recent paper (G. G. Wang et al. Nature Cell Biol. 9, 804–812; 2007) captured my attention because it dissects how one genetic change leads to epigenetic changes that ultimately cause leukaemia.

The work focuses on an abnormal fusion protein — produced after part of one gene fused, or translocated, with part of another — and narrows down its cancer-causing properties to a particular region of the protein. This region mediates an epigenetic change: it adds a methyl group to one amino acid of a histone, part of a gene's packaging in the nucleus.

The team found that the fusion protein misdirects its methylation to the histones that package HoxA genes, triggering further miscoding of the histones. This activates the genes, which promote self-renewal of blood-cell precursors, contributing to leukaemia.

I wonder if the interactions could be traced back even further. Given the role of epigenetics in stabilizing chromosomes; might it have been epigenetic miscoding that made the gene susceptible to translocation in the first place?

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University of California, San Francisco, USA

A cancer geneticist delves into family matters.

A mystery lies at the heart of a small family of growth signalling enzymes (K-Ras, H-Ras and N-Ras), which are widely mutated in human cancers. In culture, all three enzymes have similar functions, but different ras genes are associated with cancers in different tissues.

My laboratory, for instance, noted more than 25 years ago that skin cancers show activation of H-ras. Others have demonstrated that lung, colon and pancreatic cancers show activation of K-ras, whereas N-ras is the oncogene of choice in melanomas and some leukaemias.

What determines this intriguing specificity? Are the enzymes' functions somehow modified in certain tissues in vivo? Or is it regulation of the genes, affecting where and when they are expressed, that matters?

We may get some answers by following the lead of an elegant study (N. Potenza et al. EMBO Rep. 6, 432–437; 2005). In this work, the authors knocked out K-ras in mice, but simultaneously replaced the gene with its close relative H-ras, doctored to have the regulatory elements of K-ras. Mice can survive without the H-ras or N-ras genes (or even both of them) but usually die if K-ras is deleted. These mice, despite lacking K-ras, were viable and lived to a ripe old age.

This important observation provides novel opportunities to probe the mechanisms of cancer initiation. Are the mice lacking K-ras now resistant to the lung and pancreatic cancers that are normally linked to K-ras? If yes, this would indicate a true requirement for the K-Ras protein in lung-cancer development; if not, the focus would switch to regulation.

A straw poll of Ras cognoscenti suggests that opinion is for now divided, but my group and others are working on this mouse model, and hope to have answers soon.

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Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

A geneticist rebuts criticism of cancer genome projects.

What do you learn if you sequence 13,000 genes in 11 breast and 11 colorectal cancer samples? The question taps into an intense debate about how best to identify genes relevant to human cancer.

Last year, researchers reported the results of a survey such as the one described (T. Sjöblom et al. Science 314, 268–274; 2006). They found that each tumour contains, on average, 90 mutant genes — an unexpectedly high number. They also defined mutation spectra that were specific to colon and breast tumours, including the intriguing observation that the DNA letter sequence CG was swapped for GC at high frequency in breast tumours. This could be due to an uncharacterized DNA repair defect or differential carcinogen exposure.

I consider this report a step towards answering key questions in cancer biology, such as how many genes are mutated in cancer, how many mutations are required for cancer, and whether accumulation of genetic alterations in cancer cells drives tumour progression.

But others disagree. Many labs see large-scale sequencing of cancer genomes as unfocused and expensive fishing experiments. I have been doing genomics experiments since the dawn of this era, and have often faced this criticism.

But just this one study has identified more genes mutated in human cancer than thousands of investigators have found over past decades. And another recent, large-scale sequencing project pinpointed close to 120 mutant kinase enzymes that may have a role in human cancers (C. Greenman et al. Nature 446, 153–158; 2007).

Both cases show that the outcome of unbiased, genome-wide studies may not be what we expect, which is exactly why they're worth doing.

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