Biology subjects

Abba, M.

Publications and source records attributed to Abba, M..

9 recordsLinked to original sources

bioRxiv2026

Kaposi Sarcoma Herpes Virus Reprograms Mesenchymal Cell Glycosylation to control platelet-derived growth factor receptor A signaling

Kaposi sarcoma-associated herpesvirus (KSHV) reprograms host cellular pathways to promote viral persistence and tumor development by supporting the survival and expansion of infected and bystander cells. Among the signaling axes implicated in this process, oncogenic activation of receptor tyrosine kinases, particularly platelet-derived growth factor receptor alpha (PDGFRA), is a well-established hallmark of Kaposi sarcoma pathogenesis. However, the impact of virus-driven cell surface glycosylation changes in PDGFRA-associated signaling remains uncertain. Here, we identified a critical role for KSHV in reshaping the glycosylation landscape of mesenchymal stromal cells (MSCs), thereby reprogramming PDGFRA signaling. We show that KSHV infection enhances a unique glycan profile in human and mouse MSCs, enriched in branched complex N-glycans with limited (2-6) sialylation, Transcriptomic analyses of KSHV-infected MSCs and Kaposis Sarcoma patient samples revealed a coordinated dysregulation of pathways involved in carbohydrate metabolism, nucleotide-sugar transport, and sialic acid turnover, with a particular focus on sialic acid turnover (NPL/NEU3), the UDP-N-acetylglucosamine transporters SLC35A3/B4, and complex N-glycan elongation (MGAT5/B3GNT2/B4GALT1) as critical nodes underlying reduced (2-6) sialylation and increased N-glycan branching. This remodeled glycan landscape contributes to create a permissive context for galectin-1 (Gal-1) binding, which in turn enhances PDGFRA activation and downstream signaling. These findings identify an integral component of KSHV-driven mesenchymal cell reprogramming, unveiling a lectin-dependent mechanism of RTK activation in Kaposi sarcoma pathogenesis.

Cancer Biology↗

bioRxiv2025

Primary CD34+ cells of patients with VEXAS syndrome are highly sensitive to targeted treatment with TAK-243 and pevonedistat

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an autoinflammatory disease characterized by somatically acquired UBA1 mutations in hematopoietic stem cells. VEXAS patients present with significant therapeutic challenges such as severe treatment-resistant inflammation and predisposition to myeloid malignancies. In this study, we evaluated the efficacy of TAK-243, a UBA1 inhibitor, and pevonedistat, a NEDD8 inhibitor, in vitro on primary CD34+ hematopoietic stem and progenitor cells (HSPCs) from patients with VEXAS syndrome (n=5), myelodysplastic neoplasms (MDS) (n=10), as well as healthy controls (n=10). Our findings revealed that VEXAS patient-derived HSPCs exhibited significantly higher sensitivity to both TAK-243 (IC50: 22 nM) and pevonedistat (IC50: 553 nM) compared to MDS (IC50: 133 nM and 1048 nM, respectively) and healthy controls (IC50: 192 nM and 1107 nM, respectively) as demonstrated by reduced cell viability. Furthermore, VEXAS CD34+ cells exhibited significantly higher levels of apoptosis after treatment with both inhibitors. These results suggest that TAK-243 and pevonedistat selectively target UBA1-mutated progenitor cells, and indicate a broad therapeutic window in which malignant cells are eradicated but healthy hematopoiesis is not yet compromised. This study provides a strong rationale for further clinical investigation of TAK-243 and pevonedistat as targeted therapies for VEXAS patients, offering hope for improved management of this clinically challenging disorder and contributing to our understanding of its underlying molecular mechanisms.

cancer biology↗

bioRxiv2025

B-cell-Specific Wwox Deletion Promotes Plasmablastic Tumor Development and Pro-Inflammatory Signatures in a Myeloma Mouse Model

Deletions and translocations affecting WWOX accompanied by loss of expression are frequently observed in B cell neoplasms and are linked to poor prognosis. Our previous research showed that Wwox deletion early in B cell development induces genomic instability, neoplastic transformation, and monoclonal gammopathies in mice. In this study, by crossing Cd19 Wwox knockout (KO) with Vk*MYC myeloma model mice, we generated a model with concurrent Wwox deletion and MYC activation, reproducing two common oncogenic alterations in B and plasma cell cancers. We observed that Vk*MYC:Wwox KO mice exhibited significantly reduced survival rates primarily due to the development of plasmablastic plasmacytomas and lymphomas. Transcriptome profiling from bone marrow derived Cd138+ plasma cells and plasmablastic tumors revealed enrichment of biofunctions related to tumorigenic phenotype and inflammation activation upon Wwox deletion in Vk*MYC mice. Wwox KO plasmablastic tumors displayed mutations affecting classical cancer genes, DNA damage response (DDR) genes, as well as overexpression of Aid/Apobec family members associated to hypermutation and DDR mutational signatures. These findings illustrate the significant pathobiological effects of B cell specific Wwox deletion and support a relevant role for WWOX loss of function in B cell neoplastic progression towards more aggressive phenotypes.

cancer biology↗

bioRxiv2025

SPARC is a new driver of early breast tumor progression via TGF-β -dependent mechanism.

Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor of invasive ductal carcinoma (IDC). The challenge lies in discriminating between DCIS progressors and DCIS non-progressors, often resulting in over- or under-treatment in many cases. Membrane type 1 (MT1)-matrix metalloproteinase (MMP) has been previously identified as an essential gene involved in DCIS progression. Here, RNA-sequencing analysis of MT1-MMPhigh subpopulation derived from invasive breast tumors in the intraductal xenograft model was compared against a dataset of human high-grade DCIS, and Secreted Protein Acidic and Cysteine Rich (SPARC) has emerged as a master candidate involved in early breast tumor progression. We report that SPARC is up-regulated in DCIS as compared to normal breast epithelial tissues, and further increased in IDC relative to synchronous DCIS foci. We found a positive correlation between SPARC and MT1-MMP expression in DCIS lesions. At the mechanistic level, depletion of SPARC reduced MT1-MMP expression, the degradative capacity of the cells and the activation of the TGF-{beta} signalling canonical pathway. Pharmacological inhibition of the TGF-{beta} signalling pathway decreased SPARC and MT1-MMP at the mRNA and protein level, and concomitantly the cell degradative capacity and 3D cell migration. Strikingly, inhibition of the TGF-{beta} signalling pathway limits the invasive transition of breast tumors in a new triple-negative mouse intraductal syngeneic xenograft model. Moreover, high SPARC expression was positively correlated with both, TGF-{beta} and its receptor, TGFBRI, in a basal type of breast cancer collection supporting our findings. This study identifies SPARC as a new driver of early breast tumor progression via a TGF-{beta}-dependent mechanism, suggesting TGF-{beta} signaling pathway as a potential target for patients with high SPARC expression.

cancer biology↗

bioRxiv2023

Single-cell RNA sequencing identifies KSHV-infected Mesenchymal stem cell subpopulations precursors of Kaposi's Sarcoma

Kaposis sarcoma (KS) may derive from Kaposis Sarcoma Herpesvirus (KSHV)-infected human Mesenchymal Stem Cells (hMSCs) migrating into an inflammatory and angiogenic site, enhancing KS initiation. KSHV infection of primary hMSCs uncovers specific cell subpopulations, mechanisms, and conditions involved in the first steps of the KSHV-induced transformation and reprogramming process toward KS progenitor cells. The pro-angiogenic environmental conditions allowed KSHV to reprogram hMSCs closer to KS gene expression profiles and points to KSHV infection as an important factor inducing the Mesenchymal-to-Endothelial (MEndT) transition of hMSC. Single-cell RNA-sequencing analysis revealed a subpopulation of infected cells growing in a pro-angiogenic environment with both viral and host oncogenes upregulation. This highlights the importance of this condition in boosting the KSHV-induced transformation and reprogramming of hMSC towards MEndT and closer to KS gene expression profiles, reinforcing the notion of these cell subpopulations as KS precursors.

microbiology↗

bioRxiv2022

WWOX P47T loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12

WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12). This mutation affects the WW1 protein binding domain of WWOX, impairing its ability to interact with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T that phenocopies SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination, and unlike KO models that survive only for 1 month, live beyond 1 year of age. These deficits progressed with age, and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice exhibited signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. The cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions from these Wwox LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation and severe cerebellar dysfunction, activation of pathways compatible with compensatory neurogenesis along with major suppression of gene networks associated with excitability, neuronal cell differentiation and brain development. Our results show significant pathobiological effects and potential mechanisms through which WWOX LoF leads to epilepsy, cerebellar neurodegeneration, neuroinflammation, and ataxia. Additionally, the mouse model described here will be a useful tool for the study of WWOX in common neurodegenerative conditions in which it has been identified as a novel risk factor.

neuroscience↗

bioRxiv2020

USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

cancer biology↗

bioRxiv2019

RNA-sequencing analysis of a multistep and hit-and-run cell and animal model of KSHV tumorigenesis reveal the roles of mutations, CpG methylation, and viral-infection footprints in oncogenesis.

Human viral oncogenesis is the consequence of cell transformation mediated by virally encoded oncogenes in combination with host oncogenic alterations. Kaposis sarcoma (KS), caused by the Kaposis sarcoma-associated herpes virus (KSHV), is an AIDS-associated cancer characterized by angiogenesis and spindle-cells proliferation. KSHV-infected KS lesions are composed of latently-infected cells, as well as cells expressing lytic genes that have been implicated in the development of the KS angioproliferative phenotype. The existence of KS lesions with varying levels of KSHV-infected cells suggests also the existence of virus-independent \"hit-and-run\" mechanisms of sarcomagenesis, whereby viral infection irreversibly induce genetic or epigenetic oncogenic alterations in host cells. We have integrated genetic mutations, changes in expression signatures and methylation analysis to dissect genetic and epigenetic signaling pathways in an unbiased manner in the mECK36 mouse model of KSHV tumorigenesis. Pathway analysis of differential expressed genes (DEGs) showed KSHV lytic switch, DNA methylation and Epigenetic as the most regulated pathways during KSHV-dependent in vivo tumorigenesis. Methylation analysis data indicates that during the development of KSHV-infected tumors the most changes were towards hypo-methylation of tissues specific genes and oncogenic signature pathways, on the other hand during viral loss and development of KSHV-negative tumors changes are towards hyper-methylation. Mutational analysis of KSHV-infected cells and tumors revealed a set of mutations, including mutations in three inflammasome-related IFN response genes, that were absent in KSHV-infected cells but present in all KSHV-infected tumors in the same loci pointing to clonal selection \"in vivo\". This result suggests that in the context of in vivo tumorigenesis both these mutations and the virus may determine tumor growth. On the other hand, clustering analysis of mutations driving KSHV-negative tumors reveal a network comprising PDGFRA D842V, Pak1 and Nucleolin mutations implicated in cell proliferation. Our results have uncovered novel specific aspects of the interplay between host oncogenic alterations and virus-induced transcriptional effects as well as the epigenetic changes induced by KSHV infection and tumorigenesis. The existence virally-induced irreversible genetic and epigenetic oncogenic alterations support the possibility for hit-and-run KSHV sarcomagenesis which is consistent with pathological and clinical findings.\n\nAUTHOR SUMMARYWe performed whole genome RNA sequencing and CpG DNA methylation analysis in a mouse bone-marrow endothelial-lineage cells (mEC) transfected with the KSHVBac36 (mECK36 cells), that are able to form KSHV-infected tumors in nude mice, which were thoroughly characterized as KS-like tumors. This unique model allowed us to dissect genetic and epigenetic mechanisms of KSHV dependent and hit-and-run sarcomagenesis. We found that during KSHV in vivo lytic switch and KSHV-dependent tumorigenesis DNA methylation and Epigenetic regulation are among the most host-regulated pathways. CpG DNA methylation analysis during transformation supports the notion that loss of methylation (hypo-methylation) is the major epigenetic change during this process. Sequence analysis of KSHV-positive tumors revealed that KSHV tumorigenesis not only selects for the presence of the virus but also pre-existing host mutations that allow the KSHV oncovirus to express the oncogenic lytic program and creates a permissive environment of inflammation and viral tumorigenesis providing a selective advantage in vivo.

cancer biology↗

bioRxiv2019

PDGFRA Defines the Mesenchymal Stem Cell Kaposi’s Sarcoma Progenitors by Enabling KSHV Oncogenesis in an Angiogenic Environment

Kaposis sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (P(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected P(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected P(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.\n\nAUTHOR SUMMARYIdentification of the KS progenitor cell creates the possibility of studying viral oncogenesis and its determinants from its initial steps as a continuum. It also increases our understanding of pathogenic mechanisms and disease preferential tropism. Hereby we identify P(+)S-MSCs as KS progenitors, in which KSHV infection has oncogenic consequences; only when these cells are in a pro-angiogenic environment in which PDGFRA activation enables an oncogenic de-repressed KSHV epigenome. These results identify a KS-progenitor population in the P(+)S-MSCs and point to pro-angiogenic environmental conditions as essential for oncogenic viral gene expression and transformation. We designed a novel model of KSHV oncogenesis, creating a very robust platform to identify KSHV oncogenic pathways and their relationship with cellular lineages and extracellular growth environments.

cancer biology↗