Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex
Cyril Djari, … , Antoine Martinez, Anne-Marie Lefrançois-Martinez
Cyril Djari, … , Antoine Martinez, Anne-Marie Lefrançois-Martinez
Published December 1, 2021
Citation Information: J Clin Invest. 2021;131(23):e146910. https://doi.org/10.1172/JCI146910.
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Research Article Endocrinology Reproductive biology

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

Abstract

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.

Authors

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

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Figure 1

Prkar1a loss in mouse testicular somatic cells induces LCCSCTs-like lesions.

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Prkar1a loss in mouse testicular somatic cells induces LCCSCTs-like les...
(A) H&E staining of 2-week-old, 2-month-old, and 4-month-old WT and Prkar1a somatic progenitor cell KO testes (noted as prKO, Sf1:Cre,Prkar1afl/fl). Red arrowheads indicate prKO hypervascularization. Blue arrowheads indicate spermatozoa. Hy., hyperplasia; Tu., tumor; Ø, absence of spermatozoa. (B) Alizarin red S staining in 2-month-old prKO testis. Dashed lines delineate calcium accumulation areas in both ST and stroma (inset). (C) RT-qPCR analysis for LCCSCT marker transcripts (Calb2, Ctnnb1, Inha, S100a1) in 4-month-old WT and prKO testes. Statistical analysis was performed using Student’s t test or Welch’s t test. Rel, relative; quant, quantification. (D) Relative proportion of hyperplasia and tumor from 2-week-old to 4-month-old prKO testes evaluated following H&E staining. Number of each histological defect is indicated in bars. Statistical analysis was performed using 2-proportion Fisher’s test (hyperplasia/tumor proportions between 2-month-old and 4-month-old prKO testes). P = 0.0259. (E) Stromal PCNA+ cell quantification represented as percentages of cells in 2-week-old and 4-month-old WT and prKO testes. Statistical analysis was performed using Welch’s t test. (F and G) Heatmap representing the median-centered expression of significantly deregulated genes (abs[log2 FC > 1] and adj. P < 0.05) in 2-week-old (F) and 2-month-old (G) prKO testes (n = 3–4) compared with WT (n = 4). (H) Top 10 enriched GO and KEGG terms using 2-month-old prKO significant deregulated genes. Bars represent mean per group ± SD. Scale bars: 100 μm. Original magnification, ×2.12 (inset, B). *P < 0.05; ***P < 0.001.