Wahl and his team first considered the possibility that p53 does more then function as a "genome guardian" when a collaborative study with Juan Carlos Izpis-a Belmonte, Ph.D., also a professor in the Gene Expression Laboratory at the Salk Institute, revealed that this tumor suppressor also presents a barrier to somatic cell reprogramming.

To find out whether p53 inactivation does permit the emergence of tumor cells resembling stem cells, Spike and Mizuno combed through hundreds of archival gene expression profiles of breast and lung tumors, searching for stem cell-like signatures and correlating them to their p53 status.

"We found a close correlation between tumors with confirmed p53 mutations or overt p53 inactivation and gene expression patterns typical of stem cells," Spike explains. "It will influence the way we think about p53 since its loss now seems to have reverberations beyond removing the immediate cell death and proliferation barriers to tumorigenicity."

Wahl hopes that gaining a better understanding of the process that allows tumor cells to revert to a more stem-like state will reveal new targets for therapeutic intervention. "More stem-like tumors appear to be more aggressive, but they still may have residual capacity to differentiate into less aggressive cell types," he says. "If we can tap into this potential, we may be able to force these cells to differentiate to become less dangerous, which is an old idea that we need to seriously reconsider."

The closeness of the collaboration is indicated by the sharing of the first authorship between Spike and Mizuno, who is now at Chugai Pharmaceutical Co. Ltd., in Kamakura, Japan.

Source: Salk Institute