Patched and the cell of origin battle

An international team of researchers has answered a long-standing question about whether neural stem cells or granule neuron precursors are the 'cell of origin' for the childhood brain tumour medulloblastoma.

The answer is that both of them are. In a paper published today in Cancer Cell, the researchers, including Professor Brandon Wainwright from the Institute of Molecular Bioscience at the University of Queensland, examined the origin of medulloblastoma resulting from mutations in the Sonic hedgehog signalling pathway.

The Sonic hedgehog pathway is essential for the regulation of organogenesis and also controls cell division in adult stem cells.

Using a hybrid mouse model with the Patched gene knocked out, the team found that both cell types can serve as cells of origin for the tumour. Patched encodes a receptor protein for Sonic hedgehog and is an antagonist of the signalling pathway.

The team used a conditional allele of Patched that allowed it to inactivate the gene in either granule neuron precursors (GNPs) or neural stem cells. All mice with Patched-deficient GNPs developed tumours. In Patched-deficient stem cells, those stem cells that committed to the granule lineage went on to form tumours.

It also found that deletion of Patched in stem cells leads to medulloblastoma but not other brain tumours such as astrocytoma or oligodendroglioma.

"It has always been thought that cells had to mutate several times before becoming a tumour," Wainwright said. "In this study we found that some stem cells only needed to mutate once.

"They would not turn cancerous immediately, but once they had been given an instruction to turn into a more specialised cell, the mutation would take hold and they would instead turn into a tumour."

Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells is published in Cancer Cell.