Large Cell Calcifying Sertoli Cell Tumors (LCCSCTs) are among the most frequent lesions occurring in Carney complex (CNC) male 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, the 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 CNC testis lesion induction. We demonstrate that Prkar1a mutation is required in both stromal and Sertoli cells for the occurrence of LCCSCT. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to understand the human LCCSCT pathogenesis and demonstrated unprecedented 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 mouse model and human CNC testes.

中文翻译：

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PKA驱动Carney复合体中的旁分泌危机和WNT4依赖性睾丸肿瘤

大细胞钙化支持细胞肿瘤（LCCSCT）是在Carney Complex（CNC）男性患者中最常见的病变之一。尽管它们构成了因肿瘤抑制因子PRKAR1A失活导致PKA活性失活而导致的这种罕见的多发性瘤形成综合征的关键诊断标准，但LCCSCT的发病机理和起源仍然难以捉摸。产生了针对所有体细胞群体或每种细胞类型中的Prkar1a失活的小鼠模型，以破译参与CNC睾丸病变诱导的分子和旁分泌网络。我们证明，在LCCSCT的发生中，基质细胞和支持细胞都需要Prkar1a突变。整合分析，比较转录组学，