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Glioblastoma and soft tissue sarcomas are tumors characterized by poor prognosis, low overall survival and critical hallmarks that allow such tumors to evade homeostatic controlling mechanisms. Herein, we revised literature on connexins, the core gap junction forming proteins, and WT1, a transcription factor involved tumor progression, to highlight the close connection between intercellular communication deregulation and aberrant intracellular signalling. Both connexins and WT1 have been widely studied during physiological conditions and development and they hold a critical role in recapitulating such phenomena during tumorigenesis in glioblastoma and soft tissue sarcomas.