Therapy-induced senescence shapes tumor biology and treatment outcome in hepatoblastoma

Hepatoblastoma (HB) patients with high-risk disease show poor survival and require better treatment options. Due to few recurrent genetic aberrations targeted therapies remain unavailable. Characterizing dynamic cell state changes in response to chemotherapy, such as therapy-induced senescence (TIS), may unveil new targets for synthetic lethal combination treatments. Our goal is to identify TIS-specific vulnerabilities for "one-two punch" therapies using chemotherapy and senolytic drugs. HB cell lines (HepG2, Hep293TT, HUH6), PDX models, and Myc-/Ctnnb1-driven tumor mouse models were treated with doxorubicin and cisplatin. TIS was confirmed by H3K9me3/Ki67 immunofluorescence (IF) and SA-β-gal staining. In murine HB RNA sequencing and spatial IF imaging revealed senescence-associated phenotypes, such as an increased immunogenicity alongside an enhanced macrophage and T-cell infiltration. Using a large pharmacological inhibitor screen, we identified the ERAD pathway as a target for senolytic therapies. We found that TIS influences tumor biology and treatment, making senolytic 'one-two punch' therapies a promising strategy for high-risk hepatoblastoma.

Publication History

Article published online:
09 May 2025