Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance

Bone cancer (osteosarcoma) is caused by mutations in certain genes, which results in cells growing and dividing uncontrollably. In particular, a gene that produces a protein called P53 in humans is lost in all bone cancers. However, we don’t understand what happens to the bone cells when they lose P53. Although a number of studies have identified several molecular pathways that are changed in bone cancers – such as the cyclic AMP (cAMP) pathway – how these interact to cause a cancer is not well understood. Walia et al. compared bone-forming cells from normal mice with cells from mutant mice from which the gene that produces the mouse p53 protein could be removed. This revealed that the loss of p53 causes these cells to grow faster. The activity of the cAMP pathway also increases in p53-deficient cells. Further investigation revealed that the cells grow faster only if they are able to activate the cAMP pathway, and that this pathway needs to stay active for bone cancer cells to grow and survive. This suggests that inhibiting this pathway could present a new way to treat bone cancer. Walia et al. confirmed several of their findings in human cells. Future studies will now investigate how the loss of the P53 protein in humans activates the cAMP pathway, which will be important for understanding how this cancer forms. It will also be worthwhile to begin testing ways to block this pathway to determine whether it is a useful target for therapies.