Uncovering Cellular Senescence as a Therapeutic Target in Human Vestibular Schwannoma

Cellular senescence is a crucial response against cancer development. It has been demonstrated that this cellular state is a defining feature of premalignant tumors that could be important in cancer diagnosis. This tumor-supressor role of cellular senescence has not been studied so far in human vestibular schwannomas (VS). VS are benign tumors originating from the Schwann cells that form the myelin sheath of the cochleovestibular nerve. VS grow slowly and cause hearing loss both due to compression of the auditory nerve and the release of ototoxic substances. Currently, patients undergo periodic MRI, surgery, gamma-radiosurgery or radiotherapy as tumor treatment but there are no pharmacological FDA-approved therapies to treat these tumors. In this study, we used HEI-193 cell cultures and patient derived VS primary cell cultures to address whether conventional chemotherapy, mainly DNA damage drugs, may induce a senescent response in these cellular systems that makes cells susceptible to be targeted by senolytic agents. Our data show that bleomycin can induce several senescent markers in VS primary cell culture as well as in an established cell line derived from a patient with neurofibromatosis type II, HEI-193 cell line. We analyzed the SASP-related secretory profile and observed that VS expressed higher levels of cytokines, metalloproteases and other SASP components than those obtained in bleomycin-treated HEI-193 cells. Our results also show that treatment with navitoclax, a senolytic agent, decreases the viability of the bleomycin- induced senescent cells without affecting the viability of the proliferative ones. This two-punch strategy based in the combination of senogenic and senolytic agents could constitute a potential alternative for the treatment of VS.