Ccn6, also known as Wnt1-induced secreted protein 3 (WISP3), is a gene encoding a matrix-associated protein of the CCN family. It has regulatory roles in development and cancer, and is involved in pathways like Wnt/β -catenin signaling. Mutations in Ccn6 are linked to the musculoskeletal disease Progressive Pseudo Rheumatoid Dysplasia (PPRD) [2,3,4,5,6].

In mammary epithelium, conditional inactivation of Ccn6 (Ccn6-KO) in mice leads to the development of spindle metaplastic breast carcinomas (mBrCAs) with epithelial-to-mesenchymal transition (EMT). CCN6 was found to interact with the Wnt receptor FZD8 and coreceptor LRP6 on mBrCA cells, antagonizing Wnt-induced activation of β-catenin/TCF-mediated transcription. In Ccn6-KO mBrCA cells, the histone methyltransferase EZH2 was identified as a β-catenin/TCF transcriptional target. Pharmacologic inhibition of EZH2 reduced the growth and metastasis of Ccn6-KO mBrCA mammary tumors in vivo [1]. In zebrafish, morpholino-mediated depletion of Ccn6 in skeletal muscle led to reduced mitochondrial respiratory complex assembly and activity, associated with muscle mitochondrial and architectural anomalies [6].

In conclusion, Ccn6 is crucial for maintaining normal cellular functions. Its role as a tumor suppressor in mBrCAs is demonstrated through Ccn6-KO mouse models, highlighting potential therapeutic strategies targeting the β-catenin or EZH2 pathways. In the musculoskeletal system, studies in zebrafish suggest Ccn6 is essential for mitochondrial integrity and muscle function, which may be relevant to understanding PPRD [1,6].