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

Abstract

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

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00930-15.

ACKNOWLEDGMENTS

We thank the animal care staff of ALECs-SFP (Lyon, France) and ANICAN (CRCL-Lyon, France) for maintenance of mouse strains. We are grateful to B. Sosa-Pineda (St. Jude Children's Research Hospital, Memphis, TN) for the anti-Pax4 antibody. We thank Tamsin Lindström (Stockholm, Sweden) for critical reading and editing of the manuscript.

This work was supported by La Ligue contre le Cancer (CD42 and CD69), Lyon I University, l'Agence Nationale de Recherche (grant SVSE2 ANR10BLAN124004), and the European Foundation for the Study of Diabetes (EFSD/AZ cellular plasticity program 2014). D.R. was supported by fellowships from the French Ministry of Education and Research and La Ligue.

D.R. and P.B. conceived and designed the experiments. D.R., J.C., A.H., R.J., R.B., D.G., R.T., M.C.-B., and P.B. performed the experiments and analyzed the data. O.A., O.R., and C.X.Z. contributed reagents and provided advice on experiments. D.R., C.X.Z., O.R., O.A., and P.B. discussed the results. P.B. wrote the manuscript.

We have no conflicts to disclose.

Additional information

Funding

Olov Andersson thanks the Ragnar Söderbergs foundation, Swedish Research Council and Strategic Research Initiative in Stem Cells and Regenerative Medicine, for support.