biostudies-literatureNduru DPrincess Takamatsu Cancer Research FundMedical Research Center Initiative for High Depth OmicsNanken-KyotenFoundation for Promotion of Cancer Research in JapanKobayashi Foundation for Cancer ResearchMultilayered Stress DiseasesJapan Science and Technology AgencyJapan Society for the Promotion of Science353-363https://www.ebi.ac.uk/biostudies/studies/S-EPMC12861111biostudies-literatureUnknown117(2)Malignant transformation involves the acquisition of proliferative advantages by cells, often through the dysregulation of key signaling pathways. The Hippo pathway effectors YAP and TAZ are well-established regulators of cell proliferation, and their aberrant activation is linked to tumorigenesis in various cancers. However, the molecular mechanisms by which YAP and TAZ sustain malignant transformation remain unclear. In this study, we employed an in vitro transformation model using immortalized mouse embryonic fibroblasts (iMEFs) constitutively expressing active YAP or TAZ. We demonstrated that YAP or TAZ hyperactivation is sufficient to induce malignant transformation, and that the removal of these proteins reverses the transformed phenotype, indicating their necessity for both tumor inCancer scienceA YAP/TAZ-CDC6 Axis Initiates and Maintains Malignant Transformation.PMC12861111JPMJFR226J24H0086424H00865Ohta YMoroishi TNgurari SNduru DNiimura MNita AfalseA YAP/TAZ-CDC6 Axis Initiates and Maintains Malignant Transformation.Malignant transformation involves the acquisition of proliferative advantages by cells, often through the dysregulation of key signaling pathways. The Hippo pathway effectors YAP and TAZ are well-established regulators of cell proliferation, and their aberrant activation is linked to tumorigenesis in various cancers. However, the molecular mechanisms by which YAP and TAZ sustain malignant transformation remain unclear. In this study, we employed an in vitro transformation model using immortalized mouse embryonic fibroblasts (iMEFs) constitutively expressing active YAP or TAZ. We demonstrated that YAP or TAZ hyperactivation is sufficient to induce malignant transformation, and that the removal of these proteins reverses the transformed phenotype, indicating their necessity for both tumor in2026-01-01T00:00:00Z2026 Feb2026-06-19T04:46:04.499Z2026-06-19T03:07:20.695ZS-EPMC128611114131673710.1111/cas.70279