👤 Adeboye O Osunkoya

Testicular adult granulosa cell tumors (AGCTs) are rare and show several clinical, pathological, and molecular differences with their ovarian counterparts. FOXL2 p.Cys134Trp, the ubiquitous molecular driver of ovarian AGCTs, is infrequent (~ 7%) in testicular AGCTs. Recently, FGFR1 hotspot mutations were reported as a potentially "alternative molecular driver" in FOXL2-wild type (WT) ovarian AGCTs. A systematic assessment of FGFR1 status has not been performed in testicular AGCTs. Recently, our group analyzed a series of twenty testicular AGCTs using two NGS panels that lacked coverage of FGFR1. Among twelve cases analyzed successfully, none harbored pathogenic FOXL2 variants. In this study, we reassessed the tumors from our prior series with an NGS panel that covers FGFR1. Among the 14 tumors (70%) that were sequenced successfully, none harbored pathogenic FGFR1 variants. Considering the AGCTs assessed in this study and those previously reported in the literature, none of the 24 tumors analyzed to date have shown pathogenic FGFR1 variants. The present study reinforces the concept that testicular sex cord-stromal tumors classified as AGCTs are different from ovarian counterparts. Show less

Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Here, we report that PTEN deficiency induced Krüppel-like factor 5 (KLF5) acetylation and that interruption of KLF5 acetylation orchestrated intricate interactions between cancer cells and CAFs that enhance FGF receptor 1 (FGFR1) signaling and promote tumor growth. Deacetylated KLF5 promoted tumor cells to secrete TNF-α, which stimulated inflammatory CAFs to release FGF9. CX3CR1 inhibition blocked FGFR1 activation triggered by FGF9 and sensitized PTEN-deficient prostate cancer to the AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rationale for combined therapies using inhibitors of AKT and CX3CR1. Show less