Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

• Published in: The Journal of clinical investigation 2021-12, Vol.131 (23), p.1-18
• Main Authors: Djari, Cyril, Sahut-Barnola, Isabelle, Septier, Amandine, Plotton, Ingrid, Montanier, Nathanaëlle, Dufour, Damien, Levasseur, Adrien, Wilmouth, Jr, James, Pointud, Jean-Christophe, Faucz, Fabio R, Kamilaris, Crystal, Lopez, Antoine-Guy, Guillou, Florian, Swain, Amanda, Vainio, Seppo J, Tauveron, Igor, Val, Pierre, Lefebvre, Hervé, Stratakis, Constantine A, Martinez, Antoine, Lefrançois-Martinez, Anne-Marie
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Apoptosis; Care and treatment; Carney Complex - genetics; Carney Complex - metabolism; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Diagnosis; Disease Models, Animal; Gene Expression Profiling; Genes, Tumor Suppressor; Humans; Life Sciences; Male; Mice; Mice, Knockout; Mutation; Oligonucleotide Array Sequence Analysis; Paracrine Communication; Phenotype; Pigmentation; Protein kinases; Risk factors; Seminiferous Tubules - metabolism; Sertoli Cells - cytology; Testicular cancer; Testicular Neoplasms - metabolism; Testis - metabolism; Transcriptome; Wnt proteins; Wnt4 Protein - metabolism
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI146910

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.