Progression towards cure for cancer by Utrecht University
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Scientists from Utrecht University offer a new explanation for one of the greatest mysteries in the field of cancer research. Loss of often mutated tumor suppressor genes appears to have two opposite effects: it can promote cell proliferation or lead to a halt in cell division depending on the degree of gene loss. These observations support the idea that only mutations that incompletely inactivate the genes yield a selective advantage for cancer cells.
Partial loss of function leads to tumor growth and inhibits cell differentiation, while complete inactivation results in an acute cessation of cell proliferation. These observations support our idea that only mutations that incompletely inactivate the SWI / SNF components offer a selective advantage for cancer cells. Such mutations eliminate tumor suppressor activity, but leave the essential role of the SWI / SNF complex intact, “explains last author Sander van den Heuvel.
Remarkably, 20 percent of all human cancers contain mutations that affect the SWI / SNF protein complexes, as recently discovered. Several explanations have been suggested to explain the unusual pattern of SWI / SNF mutations. One possibility is that the mutated protein leads to SWI / SNF complexes with abnormal activities, another explanation is that the mutated protein inactivates the normal protein, or that the function of SWI / SNF complexes is dose dependent.
The Van den Heuvel group now strongly supports dose-dependent functions, based on a systematic analysis of the function and deregulation of SWI / SNF genes in an animal model, the nematode Caenorhabditis elegans. A previous study by the group revealed a strong tumor-suppressing role of the SWI / SNF complex in this animal. “The strength of our approach is that the effect of mutating different SWI / SNF components can be investigated in the same cell type and during well-defined moments in development,” said Van den Heuvel.
The current study investigated the contribution of different SWI / SNF complex proteins by various techniques, including inducible gene manipulation based on CRISPR / Cas9 technology. Under well-controlled conditions, the different SWI / SNF components all behaved the same way: decreased function led to over-proliferation, and complete inactivation actually halted cell division.Unusual pattern
The findings explain why an unusual pattern of gene mutations is found in human cancer. “The cancer cells cannot just lose the SWI / SNF genes; mutations are selected that partially inactivate the complex, so that the tumor suppressor activity is lost while the critical function remains intact. This also indicates that the dependence of the remaining SWI / SNF function can be exploited to prevent the spread of SWI / SNF mutant cancer cells,” said Van den Heuvel. “Given the similarities between SWI / SNF mutated worms and human cancer cells, further genetic studies in this animal model may help uncover vulnerabilities of SWI / SNF-mutated tumor cells, which may ultimately contribute to highly specific anti-cancer therapies.”
Source: Utrecht University