New insights on how brain tumors spread and become resistant to therapy
Fredrik Swartling’s group at Uppsala University/SciLifeLab and Olle Sangfelt group at Karolinska Institutet have jointly discovered that the usually protective protein FBW7 is commonly mutated and inactivated in brain tumor cells in children. This leads to a block of degradation of the stem cell protein SOX9 and gives rise to tumors that spread more easily and are more difficult to treat. The study has recently been published in the scientific journal EMBO Journal.
“Our findings are not unique to childhood brain tumors. We believe this is a central mechanism for different types of cancer since an American research group have at the same time obtained similar results as ours, but instead in colon, skin and lung tumors.” says Fredrik Swartling.
The study showed that the SOX9 protein becomes more stable in the tumor cell when FBW7 is mutated, which can cause more harm to the patient. For instance, the tumor can spread more easily and it gets more resistant to standard treatment with cytotoxic drugs.
The researchers examined the protein levels of SOX9 in malignant childhood brain tumors from more than 140 patients together with scientists in Germany. They discovered that SOX9 is more stable in tumors that more easily metastasize. In laboratory experiments the researchers mimicked the way SOX9 is stabilized in brain tumor cells and showed how SOX9 turned on 40 to 50 genes in the tumor to make it more resistant to chemotherapy and more prone to spread.
“We also identified a way to inhibit the SOX9 stabilization by treating the tumors with small molecular drugs, which made them less resistant to chemotherapy again.” says Olle Sangfelt.
At the molecular level, tumors from various patients can often be quite different from each other, even though they belong to the same type of cancer. Certain childhood brain tumors have for instance high levels of SOX9 whereas others have relatively low levels. If it would be possible to identify tumors that have an aberrantly stabilized SOX9 protein, caused by inactivation of FBW7, the drugs tested in this study could be used to prevent tumor spread in these patients and improve their response to standard chemotherapy.
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