Large-cell calcifying Sertoli cell tumors (LCCSCTs) are among the most frequent lesions occurring in male Carney complex (CNC) patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A, leading to unrepressed PKA activity, LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the induction of CNC testis lesions. We demonstrate that the Prkar1a mutation was required in both stromal and Sertoli cells for the occurrence of LCCSCTs. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to the understanding of human LCCSCT pathogenesis and demonstrated PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in a mouse model and in human CNC testes.
Cyril Djari, Isabelle Sahut-Barnola, Amandine Septier, Ingrid Plotton, Nathanaëlle Montanier, Damien Dufour, Adrien Levasseur, James Wilmouth Jr., Jean-Christophe Pointud, Fabio R. Faucz, Crystal Kamilaris, Antoine-Guy Lopez, Florian Guillou, Amanda Swain, Seppo J. Vainio, Igor Tauveron, Pierre Val, Hervé Lefebvre, Constantine A. Stratakis, Antoine Martinez, Anne-Marie Lefrançois-Martinez