Posterior fossa A (PFA) ependymoma is the most common and most feared molecular subgroup of childhood ependymoma, striking the youngest patients and defying even the most aggressive combinations of surgery and radiotherapy. Now, an international team reporting in Acta Neuropathologica has uncovered the biological engine behind the deadliest slice of this already grim group: loss of a chunk of chromosome 6q that deletes a gene called LATS1, unleashing a growth-control pathway known as Hippo. Crucially, the work shows that the resulting vulnerability can be attacked with experimental drugs already moving through clinical development for other cancers.
Ependymoma is the second most common malignant brain tumour in children, and PFA is its most frequent subgroup. Roughly half of patients relapse despite maximal tumour resection followed by focal radiotherapy, and only about a quarter of relapsed children survive beyond five years. Within PFA, tumours carrying chromosomal instability, in the form of gain of chromosome 1q or loss of chromosome 6q, form an ultra-high-risk subset for whom standard treatment is rarely curative. Previous work explained part of the 1q story, showing that extra copies of MDM4 suppress p53 signalling and that the enzyme UCK2 may render 1q-gain tumours sensitive to 5-fluorouracil, a hypothesis now being tested in North American and European trials. The 6q story, however, remained a black box.
The new study, led by Andrew Donson and Andrea Griesinger at Children’s Hospital Colorado together with Timothy Ritzmann at the University of Nottingham and collaborators in Manchester, Toronto and Heidelberg, reanalysed a large international cohort of 101 children with recurrent, methylation-classified PFA ependymomas. The numbers are stark. At first diagnosis, 6q loss appears in only a small minority of tumours, around four percent in isolation and eight percent when combined with 1q gain. But at first recurrence, 34 percent of tumours carry 6q loss, rising to 47 percent by second recurrence and 69 percent by third and later recurrences. Tumours harbouring 6q loss accounted for 45 percent of all deaths in the cohort, and by late recurrence essentially all 1q-gain tumours had also acquired 6q loss, explaining the catastrophic outcomes of tumours carrying both lesions.
To find the gene driving this behaviour, the team homed in on an autopsy sample with a focal deletion on 6q spanning 13.6 megabases, a region containing 60 genes of which eight are documented tumour suppressors. The decisive clue came from partial deletions: among 60 cases of 6q loss, ten had only partial deletions, and every one of those partial deletions encompassed the LATS1 locus. LATS1, or Large Tumour Suppressor Kinase 1, is a well-established brake on cell proliferation in lung, breast, gastric, liver, kidney, colorectal and blood cancers. Patients with partial versus whole 6q loss fared equally badly, with median overall survival near 50 months in both groups, arguing that LATS1 loss, not deletion size, defines the aggressive phenotype.
Bulk RNA sequencing confirmed that LATS1 transcript levels are markedly reduced in 6q-loss tumours, which showed the lowest LATS1 expression of any paediatric brain tumour type examined, and that expression falls further with each successive recurrence. The 6q-loss tumours also had significantly higher Ki-67 proliferation indices, pointing to an intrinsically more proliferative state. To test causality, the researchers used lentiviral vectors to force LATS1 expression back into two 6q-loss PFA cell lines, MAF-811 and MAF-928. Restoring the protein reliably suppressed proliferation in both lines, while 6q wild-type ependymoma and paediatric glioblastoma comparator lines kept growing normally, evidence that these tumour cells have become dependent on LATS1’s absence.
The mechanistic thread runs through the Hippo pathway, an ancient signalling cascade that controls organ size and cell fate. In healthy cells, LATS1 phosphorylates the co-transcriptional activator YAP at a specific site, serine 127, trapping it in the cytoplasm and marking it for degradation. When LATS1 is lost, YAP escapes into the nucleus and teams up with TEAD family transcription factors to drive pro-growth gene programs. Immunohistochemistry on 75 PFA tumours showed significantly elevated nuclear and cytoplasmic YAP in 6q-loss cases, and reintroducing LATS1 into MAF-811 cells raised phospho-YAP levels, confirming the pathway’s functional restoration. The researchers note that this mechanism mirrors findings in other ependymoma variants, including rare YAP1-fusion supratentorial tumours and NF2-mutant spinal ependymomas, suggesting Hippo dysregulation is a recurring theme across the disease.
Among the TEAD factors, TEAD2 emerged as the standout. Its RNA was significantly elevated in 6q-loss tumours and rose across successive recurrences, and it ranked 45th out of 28,595 transcripts for correlation with shortened time to progression. High TEAD2 target-gene activity predicted poor progression-free survival with a hazard ratio of 3.2. A prominent TEAD2 target, DNMT1, a DNA methyltransferase that silences tumour suppressors and locks cells into a stem-like state, dropped sharply after LATS1 knock-in, tying the genetic lesion to a concrete epigenetic output.
The therapeutic payoff came from two classes of experimental compounds. The TEAD palmitoylation inhibitor VT107, an analogue of the clinical-stage agent VT3989, showed high nanomolar potency against both 6q-loss cell lines while sparing most comparator paediatric brain tumour lines. Even more striking was the TEAD-targeted PROTAC degrader H122, a proteolysis-targeting chimera that recruits cellular disposal machinery to destroy TEAD proteins. The 6q-loss lines were killed at low single-digit to double-digit nanomolar concentrations, roughly one hundred times more sensitive than to VT107, and Western blots confirmed complete TEAD degradation within four hours. With the first-ever PROTAC, vepdegestrant, recently FDA-approved for breast cancer, this drug class offers a credible route to the clinic for ependymoma patients.
Spatial transcriptomics added a final, telling layer. Using Xenium single-molecule imaging on more than one million cells from 14 tumour sections, the team mapped TEAD2 expression across distinct neoplastic cell populations. TEAD2 was highly enriched in undifferentiated, stem-like ependymoma cells known as UEC-A, including their proliferative subpopulation, in both 6q-loss and wild-type tumours. The finding suggests these progenitor-like cells, previously linked to oncofetal reprogramming and relapse, may be the engine of PFA aggression, driven by TEAD2 much as gain-of-function TEAD signalling expands the neural progenitor pool during development.
The authors argue that 6q status should be incorporated into risk stratification and future trials of recurrent PFA ependymoma, and that Hippo-targeted therapy has near-term translational potential for these children, for whom relapse is currently a terminal event. A phase 1/2 trial of VT3989 in mesothelioma has already shown partial responses and stable disease, and a phase 3 study is planned, offering a shortcut to paediatric testing. Much work remains, including preclinical 6q-loss models to evaluate candidate inhibitors, but the study delivers what the field has lacked: a defined molecular driver of ultra-high-risk PFA ependymoma and, for the first time, a druggable path against it.
Subject of Research: LATS1 deletion on chromosome 6q and Hippo pathway activation in ultra-high-risk posterior fossa A ependymoma
Article Title: Chromosome 6q mediated loss of LATS1 tumour suppression as a targetable mechanism of ultra-high-risk posterior fossa A ependymoma
Article References: Chromosome 6q mediated loss of LATS1 tumour suppression as a targetable mechanism of ultra-high-risk posterior fossa A ependymoma. (n.d.). https://doi.org/10.1007/s00401-026-03098-z
Image Credits: AI Generated
DOI: 10.1007/s00401-026-03098-z
Keywords: ependymoma, PFA ependymoma, LATS1, chromosome 6q loss, Hippo pathway, YAP, TEAD2, tumour suppressor, PROTAC, VT107, pediatric brain tumour, spatial transcriptomics
News Source: Nathaniel Bowman. (October 13, 2026). Lost Tumour Suppressor on Chromosome 6q Drives Deadly Childhood Brain Cancer and Reveals a Drug Target. Scienmag.
