Another piece of the cancer puzzle solved

Scientists from Utrecht University provide an explanation for one of the great enigmas in the cancer field. Loss of common tumor suppressor genes can either enhance cell proliferation or lead to acute arrest of cell division, depending on the degree of loss. These observations support the idea that only mutations that incompletely inactivate the genes provide a selective advantage for cancer cells. The researchers publish their results May 20 in Science Advances.

Mutations in so-called SWI/SNF genes are common in human cancer, but the spectrum of these mutations is unusual: it includes frequent inactivation of only one of the two copies of the gene. In the new study, the group of Sander van den Heuvel (Biology Department, IBB) demonstrates that SWI/SNF loss can have one of two opposite outcomes, which is determined by the level of residual function.

Loss of tumor suppressor genes can have one of two opposite outcomes.

“Partial loss of function leads to tumor growth and interferes with cell differentiation, while complete inactivation results in an acute arrest of cell proliferation. These observations support our idea that only mutations that incompletely inactivate the SWI/SNF components provide a selective advantage for cancer cells. Such mutations eliminate a tumor suppressor activity, but leave the essential role for the SWI/SNF complex intact”, last author Sander van den Heuvel explains.

Remarkably, 20 percent of all human cancers contain mutations that affect the SWI/SNF protein complexes, as was only recently discovered. Various explanations have been proposed to explain the unusual pattern of SWI/SNF mutations. The possibilities include that the mutant protein creates SWI/SNF complexes with abnormal activities, that the mutant protein inactivates the normal protein, or that the function of SWI/SNF complexes is dosage dependent.

Dosage-dependent

The Van den Heuvel group now provides strong support for dosage-dependent functions, based on a systematic analysis of the function and deregulation of SWI/SNF genes in a genetic animal model, the nematode Caenorhabditis elegans. A previous study from the group revealed a critical tumor suppressor function for the SWI/SNF complex in this animal. “The strength of our approach is that the effect of mutating different SWI/SNF subunits can be examined in the same cell type and during well-defined developmental decisions”, Van den Heuvel says.

The current follow-up examined the contribution of different components of the SWI/SNF complex through various techniques, including inducible gene manipulation based on CRISPR/Cas9 technology. In well-controlled conditions the different SWI/SNF components all behaved the same, with reduced function leading to overproliferation, and complete inactivation preventing cell division.

Unusual pattern

“The data explain why an unusual pattern of gene mutations is found in human cancer. The cancer cells cannot simply delete the SWI/SNF genes; mutations are selected that partly inactivate the complex, so that the tumor suppressor activity is lost while the critical function is left intact. The new data also support that the dependence on the remaining SWI/SNF function may be exploited to prevent the expansion of SWI/SNF mutant cancer cells”, Van den Heuvel says. “Given the similarities between SWI/SNF mutant worms and human cancer cells, further genetic studies in this animal may help discover vulnerabilities of SWI/SNF mutant tumor cells, which ultimately may contribute to highly specific anti-cancer therapies”.

Publication

Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferation in vivo. Science Advances, 20 mei 2020. Aniek van der Vaart* , Molly Godfrey*, Vincent Portegijs*, Sander van den Heuvel*.

*Authors affiliated with Utrecht University