The etiology of autism spectrum disorders has proved difficult to decipher, despite a wealth of evidence for genetic and environmental causes. But in April, four studies yielded a raft of new candidate genes for these neurological disorders, offering new avenues for autism research (Nature 485, 237–241;242–245; 246–250, 2012; Neuron 74, 285–299, 2012).
The four teams—headed up by researchers from Massachusetts General Hospital and Harvard Medical School in Boston, Yale University in New Haven, Connecticut, the University of Washington in Seattle and the Cold Spring Harbor Laboratory in Long Island, New York—sequenced the coding regions of the genomes from almost 1,000 individuals with 'sporadic' autism as well as unafflicted members of their families. This process identified more than 100 spontaneously occurring mutations that might contribute to autism risk, although few genes were found that were mutated in more than one individual with the disease. These results suggest the genetics of autism are very heterogeneous and support models where many genes contribute to risk.
Intriguingly, two of the studies indicated that the de novo mutations contributing to autism were more likely to be inherited from the father of the affected child and were positively correlated with paternal age. The importance of paternal age in autism was further hinted at by a paper published in August by researchers from deCODE Genetics in Iceland, which revealed that older fathers transmit more de novo mutations to their offspring than younger fathers (Nature 488, 471–475,2012). The next—and formidable—challenge will be to dissect the functional consequences of these newly identified genetic variants in autism. —MS
The importance of the tumor microenvironment, as well as the means by which cancer cells manipulate their adoptive niches, came into the foreground this year. Several groups, for example, provided key insights into how tumor cells subvert the natural inhibitory mechanisms that try to prevent their infiltration and growth in secondary sites. Evidence for how tumors use exosome secretion to make secondary organs more receptive to metastasis came from researchers at New York's Weill Cornell Medical College (Nat. Med. 18, 883–891, 2012). Once cancer cells have reached pliant niches, they also actively counteract tissue-derived growth-restricting inputs through novel signaling components such as the BMP inhibitor Coco, which was identified by investigators from New York's Memorial Sloan-Kettering Cancer Center (Cell 150, 764–779, 2012).
Metastatic cancer cells can also influence the immune and vascular cell components of their surroundings using paracrine signals, as reported by another Sloan-Kettering team (Cell 150,165–178, 2012). To boot, the study demonstrated that this cross-talk can protect tumor cells from the onslaught of antitumor therapy.
Even surrounding normal tissue might influence treatment response. A survey carried out at the Broad Institute in Cambridge, Massachusetts, revealed that stroma-mediated therapy resistance is a common phenomenon and that proteins secreted into the local microenvironment can make tumors insensitive to targeted therapies (Nature 487, 500–504, 2012). In a parallel study, a group from the Fred Hutchinson Cancer Research Center in Seattle uncovered how the damage to normal tissue by chemotherapy can prompt healthy cells to secrete proteins that promote the regrowth of tumor cells (Nat. Med. 18, 1359–1368, 2012). These reports and others underscore the need to put cancer therapies in context. —VA