A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC)

Colon cancer remains an important problem in healthcare. Cancer researchers are looking for new ways to detect the disease earlier and treat it more effectively. This is challenging because many of the genetic and molecular causes of colon cancer are still poorly understood. Mutations in the gene that encodes a protein called APC are one of the major causes of the disease. The APC protein normally keeps cells from growing and dividing too fast or in an uncontrolled way and is hence referred to as a tumor suppressor. For example, APC induces stem cells in the intestine to develop into specialized cells that keep the gut working normally. Mutations in tumor suppressor genes are common in many cancers. Other research has shown that cancer cells must reprogram their own metabolism – in other words, all the chemical processes that keep the cell alive – to meet the demands of proliferating rapidly. In particular, recent studies reveal that colon cancer cells produce less of a protein called mpc1, which is involved in metabolism. These discoveries raised the following questions: does APC have an additional role in maintaining normal metabolism in cells by controlling how much mpc1 is produced? Do mutations in the gene for APC lead to colon cancer because they alter the cell’s metabolism? Sandoval et al. have now discovered a connection between APC and changes in cancer cells that help them to adapt to a new metabolic program. Experiments with zebrafish – a model animal that is now commonly used in the field of cancer biology – showed that APC acts via mpc1 to regulate how the cell uses energy. This regulation goes awry in colon cells that have abnormal APC activity; however, restoring the cell’s metabolism back to normal was enough to induce cells in the intestine to develop properly. Together, these findings suggest that restoring the normal balance of energy production in colon cancer cells may be an effective way to make the cells behave normally. This hypothesis remains to be tested and, if confirmed, further studies will be needed to determine whether it will lead to new treatments for colon cancer in humans.