ActivinB Is Induced in Insulinoma To Promote Tumor Plasticity through a ß-Cell-Induced Dedifferentiation.

Loss of pancreatic ß-cell maturity occurs in diabetes and insulinomas. Although both physiological and pathological stresses are known to promote ß-cell dedifferentiation, little is known about the molecules involved in this process. Here we demonstrate that activinB, a transforming growth factor ß (TGF-ß)-related ligand, is upregulated during tumorigenesis and drives the loss of insulin expression and ß-cell maturity in a mouse insulinoma model. Our data further identify Pax4 as a previously unknown activinB target and potent contributor to the observed ß-cell dedifferentiation. More importantly, using compound mutant mice, we found that deleting activinB expression abolishes tumor ß-cell dedifferentiation and, surprisingly, increases survival without significantly affecting tumor growth. Hence, this work reveals an unexpected role for activinB in the loss of ß-cell maturity, islet plasticity, and progression of insulinoma through its participation in ß-cell dedifferentiation.