EPEN-21. EXPLORATION OF TUMOR SUPPRESSOR LATS1 LOSS IN POSTERIOR FOSSA GROUP A EPENDYMOMA WITH LOSS OF CHROMOSOME 6Q

Abstract

Abstract INTRODUCTION Chromosome 6q loss (6q-) has recently been identified as an ultra-high-risk factor in posterior fossa group A ependymoma (PFA). This study seeks to pinpoint the biological mechanism underlying the aggressive biology of PFA 6q-. We hypothesize that loss of chromosome 6q gene large tumor suppressor kinase 1 (LATS1) in PFA 6q- results in increased Hippo pathway activity that drives malignant tumor progression. LATS1 is a key negative regulator of the Hippo pathway which may represent a novel therapeutic vulnerability in 6q- PFA. METHODS We are testing this hypothesis using genomic and transcriptomic analysis of PFA patient samples, and by gene knock-in and pharmaceutical interventions of LATS1 and Hippo pathway components in PFA 6q- models. RESULTS Tumor suppressor LATS1 shows reduced expression in PFA 6q- patient samples. Although complete loss of the entire 6q arm is common in PFA 6q-, partial loss of chromosome 6q is also observed, and in all cases this partial loss encompasses the LATS1 locus on chromosome 6q. We used lentiviral transduction to knock-in LATS1 in PFA 6q- cell lines to determine the effect on tumor growth. This demonstrated loss of viability that was specific for 6q- PFA cell lines versus 6q WT control cell lines. DISCUSSION Data point to LATS1 loss being a key driver of the aggressive phenotype of PFA6q-, implicating the Hippo pathway in PFA 6q- and potential for novel therapeutic strategies.