Biology subjects

Papa, A.

Publications and source records attributed to Papa, A..

3 recordsLinked to original sources

bioRxiv2025

Genetic Ablation and Multi-Omics Profiling Reveal CEP55 as a Key Driver of Tumorigenesis in Diverse Cancer Models

BackgroundCEP55 is a centrosomal protein with emerging oncogenic roles. It is overexpressed in many cancers, where it drives genomic instability, phenocopies PTEN loss and hyperactivates the PI3K/AKT pathway, thereby promoting aggressive and therapy-resistant tumors. MethodsWe developed an inducible Cep55 knockout (KO) mouse model as well as generated primary, immortalized (SV40), and transformed (E1A/Ras) mouse embryonic fibroblasts (MEFs) for functional and proteomic assays. Tumorigenesis was studied using E1A/Ras MEF transplantation and a Pten-deficient genetically engineered mouse model (GEMM). Multi-omics apparatus including proteomics, and spatial transcriptomics, histopathology, immunobloting and functional assays were employed to elucidate underlying mechanisms. Findings were cross-validated using human cancer datasets. ResultsCep55 ablation remodeled the extracellular matrix (ECM), disrupted integrin and oncogenic signaling, reduced AKT/ERK activation, and induced stress pathways. Cep55 knockouts (KO) cells showed impaired proliferation, migration, invasion, and adhesion. In vivo, unlike the embryonic lethality observed in constitutive KOs, the inducible Cep55 deletion was well-tolerated in adult mice. Strikingly, tumors derived from Cep55-null EIA/RAS-transformed MEFs exhibited delayed onset and progression. In the genetically engineered cancer-prone mouse model, Cep55 deletion on a Pten-deficient background led to a greater than seven-fold increase in median survival. Spatial transcriptomics on cancerous tissues revealed that CEP55 regulates ECM remodeling, integrin expression, trafficking, and cell adhesion, supporting its critical role in tumor progression to metastasis. ConclusionCEP55 is dispensable for adult homeostasis but essential for tumorigenesis, especially with PTEN loss. Its deletion suppresses transformation, delays tumor growth, and prolongs survival, supporting CEP55 as a therapeutic target in PTEN-deficient cancers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/685219v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@3d81e8org.highwire.dtl.DTLVardef@1bd5a7org.highwire.dtl.DTLVardef@167ecf3org.highwire.dtl.DTLVardef@1f57b95_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Asymmetric Allostery in Estrogen Receptor-α Homodimers Drives Responses to the Ensemble of Estrogens in the Hormonal Milieu

The estrogen receptor- (ER) is thought to function only as a homodimer, but responds to a variety of environmental, metazoan, and therapeutic estrogens at sub-saturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations --receptor conformational heterodimers--mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining binding of the same ligand in crystal structures of ER in the agonist versus antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist versus antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric versus dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing new modes for ligand-dependent regulation of ER activity. SignificanceThe estrogen receptor- (ER) regulates transcription in response to a hormonal milieu that includes low levels of estradiol, a variety of environmental estrogens, as well as ER antagonists such as breast cancer anti-hormonal therapies. While ER has been studied as a homodimer, the variety of ligand and receptor concentrations in different tissues means that the receptor can be occupied with two different ligands, with only one ligand in the dimer, or as a monomer. Here, we use X-ray crystallography and molecular dynamics simulations to reveal a new mode for ligand regulation of ER activity whereby sequence-identical homodimers can act as functional or conformational heterodimers having unique signaling characteristics, with ligand-selective allostery operating across the dimer interface integrating two different signaling outcomes.

biophysics↗

bioRxiv2022

West Nile Virus spread in Europe - phylogeographic pattern analysis and key drivers

Spread and emergence of West Nile virus (WNV) in Europe have been very different from those observed in North America. Here, we describe key drivers by combining viral genome sequences with epidemiological data and possible factors of spread into phylodynamic models. WNV in Europe has greater lineage diversity than other regions of the world, suggesting repeated introductions and local amplification. Among the six lineages found in Europe, WNV-2a is predominant, has spread to at least 14 countries and evolved into two major co-circulating clusters (A and B). Both of these seem to originate from regions of Central Europe. Viruses of Cluster A emerged earlier and have spread towards the west of Europe with higher genetic diversity. Amongst multiple drivers, high agriculture activities were associated with both spread direction and velocity. Our study suggests future surveillance activities should be strengthened in Central Europe and Southeast European countries, and enhanced monitoring should be targeted to areas with high agriculture activities.

evolutionary biology↗