Chromosome 6q mediated loss of LATS1 tumour suppression as a targetable mechanism of ultra-high-risk posterior fossa A ependymoma.

Posterior Fossa A (PFA) is the most frequent and clinically aggressive ependymoma (EPN) subgroup, with relapse typically representing a terminal event despite intensive multimodal therapy. Ultra-high-risk PFA EPNs are characterised by chromosome 6q loss (6q-) with or without chromosome 1q gain (1q +). While the molecular mechanisms driving 1q+ have been elucidated, 6q- PFA pathobiology remains poorly understood. Here, we show that loss of 6q in PFA EPN results in deletion of LATS1 (Large Tumour Suppressor Kinase 1), thereby dysregulating the Hippo signalling pathway and enhancing YAP/TEAD activity. Integrated analyses of primary and recurrent PFA EPNs, incorporating clinical, multiomic, and functional assays, were performed to define the biology and therapeutic susceptibility of 6q- PFA EPNs. Cumulative 6q loss was associated with nearly half of PFA EPN-related deaths. Copy number profiling identified the LATS1 locus as recurrently deleted across all 6q- cases, including 10/60 with partial 6q deletions. Restoration of LATS1 expression in 6q- PFA cell lines re-established protein levels and suppressed proliferation. Tumour analyses showed marked Hippo pathway disruption with elevated YAP expression and TEAD2-related transcriptional activity. TEAD2 palmitoylation inhibitor VT107, and Proteolysis Targeted Chimera (PROTAC) degrader H122, exhibited PFA 6q- selective activity in vitro. TEAD2 upregulation was further observed in a previously described undifferentiated, progenitor-like population of PFA EPN cells. In conclusion, 6q loss defines an aggressive biological subset of PFA associated with dismal outcomes. Identification of LATS1 as a recurrently lost tumour suppressor implicates Hippo pathway dysregulation as a central driver of malignancy, and we identify YAP/TEAD signalling as a potential therapeutic target.