Two California teams discovered genetic machinery that cancer stem cells in high-grade brain cancers use to evade therapy. One CIRM-funded team at Cedars-Sinai in Los Angeles pinpointed a family of genes that turn off other genes that chemotherapy targets —effectively hiding them from the chemo. The other team at the University of California, San Diego (UCSD), found a culprit switch among the molecules that surround genes in the DNA.
Chemical switches like those found at UCSD control much of how our cells function. These so called epigenetic markers can toggle between on and off states and result in two cells with the same genes behaving differently. That is what the San Diego team found when they transplanted cells from the same glioblastoma brain cancer into different mice. Some readily formed new tumors and some did not.
“One of the most striking findings in our study is that there are dynamic and reversible transitions between tumorigenic and non-tumorigenic states in glioblastoma that are determined by epigenetic regulation,” said senior author Clark Chen. “This plasticity represents a mechanism by which glioblastoma develops resistance to therapy.”
The switch the cancer stem cells used in this case is called LSD1 and the researchers hope to be able to learn how to manipulate that switch to make the brain cancer stem cells more vulnerable to therapy.
The family of genes fingered by the Cedars team control the on-off status of a number of genes associated with cancer stem cells. That family, called Ets factors, is quite large but the brain tumor model used by the team allows them to quickly determine which genes are being impacted by the Ets factors.
“The ability to rapidly model unique combinations of driver mutations from a patient’s tumor enhances our quest to create patient-specific animal models of human brain tumors,” said Moise Danielpour the senior author on the study
The team’s next step: testing the function of the various Ets factors to see what their specific roles are in tumor progression.
Given the dismal five-year survival rate for high-grade brain cancers these advances in understanding their genetic machinery should push the field toward better therapy.
The Cedars team published in the journal Cell Reports and Health Canal picked up the hospital’s press release. The UCSD team published in the Proceedings of the National Academy of Sciences and Science Daily picked up the university’s press release. CIRM funds a number of projects working on new therapies for brain cancer.