Biology subjects

Varyova, Z.

Publications and source records attributed to Varyova, Z..

3 recordsLinked to original sources

bioRxiv2026

Evidence that the protein phosphatase activity of PTEN contributes to embryonic development and tumour suppression in mice

PTEN (phosphatase and tensin homologue deleted on chromosome ten) is a tumour suppressor, the function of which is impaired in many diverse cancers. It has phosphoinositide lipid phosphatase activity by which it suppresses activation of the oncogenic PI3K signalling network but in vitro also displays activity against protein substrates and is able to auto-dephosphorylate its Thr366 residue. Here we generate germline knock-in mice expressing PTEN-Y138L, a mutant enzyme which selectively lacks protein phosphatase activity and retains lipid phosphatase activity. Homozygous PtenY138L/Y138L mice die in utero before E10.5. Primary MEFs and thymocytes with only a single PtenY138L allele display normal low levels of AKT phosphorylation indicating effective regulation of PI3K signalling by endogenous PTEN-Y138L in vivo. Heterozygous Pten+/Y138L mice have reduced overall survival compared to wild type littermates and develop tumours in multiple organs. Our data imply that in addition to its lipid phosphatase activity, the protein phosphatase activity of PTEN is also required for normal embryonic development and tumour suppression.

cancer biology↗

bioRxiv2026

The breast tumor microenvironment exploits eosinophil plasticity to suppress their anti-tumor activity

Eosinophils recently emerged as mediators of anti-tumor immunity in immune checkpoint blockade (ICB) treated breast cancer patients. Yet, their role in the treatment-naive breast tumor microenvironment (TME) remains elusive. Here, we show that the breast TME shapes eosinophils into a less active state characterized by loss of Ly6C. While bone marrow and circulating eosinophils are Ly6C, this population progressively transitions into a Ly6C- state marked by reduced cytotoxicity and interferon (IFN) responsiveness during tumor progression. Further investigation of Ly6C uncovered previously unappreciated granularity of eosinophil differentiation in vitro, recapitulating the Ly6C to Ly6C- transition and associated functional loss observed in vivo. IFN stimulation partially restored the Ly6C phenotype ex vivo. Importantly, in ICB-treated tumors, Ly6C+ eosinophils positively correlated with increasing levels of IFNs, suggesting an additional mechanism by which IFNs contribute to effective ICB responses. We propose Ly6C as a key marker of eosinophil differentiation and activation, with the TME shaping eosinophils into a less cytotoxic Ly6C- state.

immunology↗

bioRxiv2025

A mouse model of PTEN Hamartoma Tumour Syndrome reveals that loss of the nuclear function of PTEN drives macrocephaly, lymphoid overgrowth, and late-onset cancer

PTEN Hamartoma Tumour Syndrome (PHTS) is a rare disorder characterized by germline heterozygous mutations in the PTEN tumour suppressor gene, leading to multi-organ/tissue overgrowth, autism spectrum disorder and increased cancer risk. PHTS individuals display heterogeneity in phenotypes, which has been linked in part to the diverse genetic alterations in the PTEN gene and the multifaceted functions of this protein. Indeed, while PTEN primarily functions as a PIP3 lipid phosphatase in the cytosol, regulating PI3K/AKT signalling, a pathway commonly deregulated in cancer, it also plays crucial roles in maintaining chromosomal stability through nuclear activities such as double strand (ds) DNA damage repair. Recent studies have identified a subset of missense PHTS variants that cause nuclear exclusion of PTEN, impairing its nuclear functions. Here, we present our findings from one such pathogenic variant, PTEN-R173C, frequently found in PHTS and somatic cancers. Using cell biological and mouse modelling approaches, we show that PTEN-R173C has higher PIP3 phosphatase activity than wild-type PTEN, resulting in effective regulation of canonical PI3K/AKT signalling. However, PTEN-R173C is unstable and excluded from the nucleus. Aligning with their near normal PI3K/AKT signalling, Pten+/R173Cmice display a low incidence of solid tumours compared to Pten+/-mice. Pten+/R173C mice also exhibit lymphoid hyperplasia and macrocephaly which correlates with compromised nuclear functions of PTEN-R173C. That nuclear functions are compromised is demonstrated by reduced dsDNA damage repair in Pten+/R173Cmice. Integrating PHTS patient data with findings from our mouse model, our study indicates that nuclear dysfunction of pathogenic PTEN variants is a key factor in predicting the onset of the different PHTS-associated phenotypes. We speculate that late-onset cancer in individuals with nuclear-excluded PTEN results from genetic alterations unrelated to PTEN itself, facilitated by impaired PTEN-mediated dsDNA damage repair.

genetics↗