Biology subjects

Boroni, M.

Publications and source records attributed to Boroni, M..

9 recordsLinked to original sources

bioRxiv2025

Resistance to BRAF inhibitors drives melanoma sensitivity to Chk1 inhibition

BRAF inhibitor-resistant melanomas (BRAFiR) acquire (epi)genetic and functional alterations that enable them to evade alternative treatments. Identifying these alterations is critical to advancing treatment strategies. Here, we explored the effect of Chk1 inhibition (Chk1i) on BRAFiR cells, revealing higher sensitivity compared to treatment-naive cells both in vitro and in vivo. Using FUCCI-labeling and time-lapse microscopy, we show that S phase progression is required for Chk1i-induced cytotoxicity in BRAFiR cells, but not in treatment-naive cells. Replication stress markers, including reduced BrdU incorporation and increased phospho-RPA and {gamma}H2AX, were exclusive to BRAFiR cells exposed to Chk1i. Untreated BRAFiR cells exhibited upregulated DNA replication genes, reduced progressing forks and increased origin firing, suggesting intrinsic replication changes. MAPK pathway reactivation in treatment-naive cells mimicked BRAFiR traits, increasing sensitivity to Chk1i. These findings indicate that Chk1i exploits elevated replication stress specifically in BRAFiR, highlighting its therapeutic potential in overcoming MAPK inhibitor resistance in melanoma.

cancer biology↗

bioRxiv2023

A multi-tissue single-cell tumor microenvironment atlas reveals myeloid-derived cell states with significant impact on clinical outcome

Tumor-associated myeloid-derived cells (MDCs) significantly impact cancer prognosis and treatment response due to their remarkable plasticity and tumorigenic behaviors. We integrated single-cell RNA-Sequencing datasets from seven different cancers, resulting in a comprehensive collection of 29 MDC subpopulations in the tumor microenvironment (TME). Distinguishing resident-tissue from monocyte-derived macrophages, we discovered a resident-tissue-like subpopulation within monocyte-derived macrophages. Additionally, hypoxia-driven macrophages emerged as a prominent TME component. Deconvolution of these profiles revealed five subpopulations as independent prognostic markers across various cancer types. Validation in large cohorts confirmed the FOLR2-expressing macrophage association with poor clinical outcomes in ovarian and triple-negative breast cancer. Moreover, the marker TREM2, commonly used to define immunosuppressive tumor-associated macrophages, cannot solely predict cancer prognosis, as different polarization states of macrophages express this marker in a context-dependent manner. This comprehensive MDC atlas offers valuable insights and a foundation for novel analyses, advancing strategies for treating solid cancers.

cancer biology↗

bioRxiv2021

Oral Lichen Planus and its relation with Oral Squamous Cell Carcinoma: new insights into the potential for malignant transformation

Oral Lichen Planus (OLP) is a chronic inflammatory disorder of unknown etiology. However, evidence suggests that it consists of an immunological process that leads to degeneration of the keratinocytes in the basal layer of the oral mucosa. Despite being recognized by WHO as a potentially malignant disorder with progression to oral squamous cell carcinoma (OSCC), the relationship between both pathologies is still controversial. Different studies have investigated factors associated with the potential for malignant transformation of OLP but it remains unclear. Through a bioinformatics approach, we investigated similarities in gene expression profiles of OLP and OSCC in early and advanced stages. Our results revealed gene expression patterns related to processes of keratinization, keratinocyte differentiation, cell proliferation and immune response in common between OLP and early and advanced OSCC, with the cornified envelope formation and antigen processing cross-presentation pathways in common between OLP and early OSCC. Together, these results reveal that key genes such as PI3, SPRR1B and KRT17, in addition to genes associated with different immune processes such as CXCL-13, HIF1A and IL1B may be involved in this oncogenic process. In addition, we performed an analysis of differentially and co-expressed genes and proposed putative therapeutic targets and associated drugs.

bioinformatics↗

bioRxiv2021

Wiring multiple microenvironment proteomes uncovers the biology in head and neck cancer

The poor prognosis of head and neck cancer (HNC) is associated with the presence of metastasis within the lymph nodes (LNs). Herein, the proteome of 140 multisite samples from a 59-HNC patient cohort, including primary and matched LN-negative or -positive tissues, saliva, and blood cells, reveals insights into the biology and potential metastasis biomarkers that may assist in clinical decision making. Protein profiles are strictly associated with immune modulation across datasets, and this provides the basis for investigating immune markers associated with metastasis. The proteome of LN metastatic cells recapitulates the proteome of the primary tumor sites. Conversely, the LN microenvironment proteome highlights the candidate prognostic markers. By integrating prioritized peptide, protein, and transcript levels with machine learning models, we identified a nodal metastasis signature in the blood and saliva. In summary, we present the deepest proteome characterization wiring multiple sampling sites in HNC, thus providing a promising basis for understanding tumoral biology and identifying metastasis-associated signatures.

cancer biology↗

bioRxiv2021

The transcriptional cofactor IRF2BP2 plays a key role in T cell homeostasis and Treg cell expansion

The levels of the co-transcriptional regulator IRF2BP2 (Interferon Regulatory Factor-2 Binding Protein-2) decrease with T cell activation and, when ectopically expressed, it reduces T cell proliferation. To further characterize the function of IRF2BP2 in T cell responses in vivo, we generated a conditional transgenic knock-in mouse that overexpresses IRF2BP2 in T lymphocytes. Overexpression of IRF2BP2 leads to a reduction in the T cell compartment of naive animals, upregulation of Foxp3 and Ifng; an increase in the frequency of regulatory T cells (Tregs), a preferential Th1 differentiation with increase of IFN-{gamma} production and a reduction of T cell proliferation, suggesting a disruption in T cell homeostasis. Interestingly, knock-in mice displayed reduced clinical and inflammatory signs of Experimental Autoimmune Encephalomyelitis (EAE) when compared to the control mice, with an augmented frequency of Treg cells. Altogether, our findings indicate that IRF2BP2 might help to control exacerbated T cell responses and point to a role for IRF2BP2 in preventing T cell autoimmunity.

immunology↗

bioRxiv2021

New SARS-CoV-2 lineages could evade CD8+ T-cells response

BackgroundMany SARS-CoV-2 variants of concern have emerged since the Covid-19 outburst, notably the lineages detected in the UK, South Africa, and Brazil. Their increased transmissibility and higher viral load put them in the spotlight. Much has been investigated on the ability of those new variants to evade antibody recognition. However, not enough attention has been given to pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses during the natural course of infection by new lineages. MethodsIn this work, we investigated the SARS-CoV-2-specific CD8+ T cell epitopes from the main variants of concern and the potential of associated mutations to trigger or hinder CD8+ T-cells response. We also estimated the populations coverage of these different lineages, considering peptide binding predictions to class I HLA alleles from 29 countries to investigate differences in the fraction of individuals expected to respond to a given epitope set from new and previous lineages. ResultsWe observed a lower populational coverage for 20B/S.484K (P.2 lineage) in contrast to an increased coverage found for 20H/501Y.V2 (B.1.351 Lineage) and 20J/501Y.V3 (P.1 lineage) compared to a reference lineage. Moreover, mutations such as Spike N501Y and Nucleocapsid T205I were predicted to have an overall higher affinity through HLA-I than the reference sequence. ConclusionsIn summary, the data in this work provided evidence for the existence of potentially immunogenic and conserved epitopes across new SARS-CoV-2 variants, but also highlights the reduced populationals coverage for the Brazilian lineage P.2, suggesting its potential to evade from CD8+ T-cell responses. Our results also may guide efforts to characterize and validate relevant peptides to trigger CD8+ T-cell responses, and design new universal T-cell-inducing vaccine candidates that minimize detrimental effects of viral diversification and at the same time induce responses to a broad human population.

immunology↗

bioRxiv2020

Senotherapeutic peptide reduces skin biological age and improves skin health

Skin aging has been primarily related to aesthetics and beauty. Therefore, interventions have focused on reestablishing skin appearance, but not necessarily skin health, function, and resilience. Recently, cellular senescence was shown to play a role in age-related skin function deterioration and influence organismal health and, potentially, longevity. In the present study, a two-step screening was performed to identify peptides capable of reducing cellular senescence in human dermal fibroblasts (HDF) from Hutchinson-Gilford Progeria (HGPS) patients. From the top four peptides of the first round of screening, we built a 764-peptide library using amino acid scanning, of which the second screen led to the identification of peptide 14. Peptide 14 effectively decreased HDF senescence induced by HGPS, chronological aging, ultraviolet-B radiation, and etoposide treatment, without inducing significant cell death, and likely by modulating longevity and senescence pathways. We further validated the effectiveness of peptide 14 using human skin equivalents and skin biopsies, where peptide 14 promoted skin health and reduced senescent cell markers, as well as the biological age of samples, according to the Skin-Specific DNA methylation clock, MolClock. Topical application of peptide 14 outperformed Retinol treatment, the current gold-standard in "anti-aging" skin care. Finally, we determined that peptide 14 is safe for long-term applications and also significantly extends both the lifespan and healthspan of C. elegans worms tested in two independent testings. This highlights the potential for geroprotective applications of the senotherapeutic compounds identified using our screening platform beyond the skin.

bioengineering↗

bioRxiv2019

Differential modulation of mouse heart gene expression by infection with two Trypanosoma cruzi strains: a transcriptome analysis

The protozoan Trypanosoma cruzi (T. cruzi) is a well-adapted parasite to mammalian hosts and the pathogen of Chagas disease in humans. As both host and T. cruzi are highly genetically diverse, many variables come into play during infection, making disease outcomes difficult to predict. One important challenge in the field of Chagas disease research is determining the main factors leading to parasite establishment in the chronic stage in some organs, mainly the heart and/or digestive system. Our group previously showed that distinct strains of T. cruzi (JG and Col1.7G2) acquired differential tissue distribution in the chronic stage in dually-infected BALB/c mice. To investigate changes in the host triggered by the two distinct T. cruzi strains, we assessed the gene expression profile of BALB/c mouse hearts infected with either JG, Col1.7G2 or an equivalent mixture of both parasites during the initial phase of infection. This study demonstrates a clear distinction in host gene expression modulation by both parasites. Col1.7G2 strongly activated Th1-polarized immune signature genes, whereas JG showed only minor activation of the host immune response. Moreover, JG strongly reduced the expression of genes for ribosomal proteins and mitochondrial proteins related to the electron transport chain. Interestingly, evaluation of gene expression in mice inoculated with the mixture of parasites showed expression profiles for both up- and down-regulated genes, indicating the coexistence of both parasite strains in the heart during the acute phase. This study suggests that different strains of T. cruzi may be distinguished by their efficiency in activating the immune system, modulating host energy and reactive oxygen species production and decreasing protein synthesis during early infection, which may be crucial in defining parasite persistence in specific organs.\n\nAuthor SummaryThe causative agent of Chagas disease, Trypanosoma cruzi, retains high genetic diversity, and its populations vary greatly across geographic locations. The T. cruzi mammalian hosts, including humans, also have high genetic variation, making it difficult to predict the disease outcome. Accordingly, this variability must be taken into account in several studies aiming to interrogate the effect of polyparasitism in drug trials, vaccines, diagnosis or basic research. Therefore, there is a growing need to consider the interaction between the pathogen and the host immune system in mixed infections. In the present work, we present an in-depth analysis of the gene expression of hearts from BALB/c mice infected with Col1.7G2 and JG alone or a mixture of both strains. Col1.7G2 induced a higher Th1 inflammatory response, while JG exhibited a weaker activation of immune response genes. Furthermore, JG-infected mice showed a notable reduction in the expression of genes responsible for mitochondrial oxidative phosphorylation and protein synthesis. Interestingly, the mixture-infected group displayed changes in gene expression as caused by both strains. Overall, we provided new insights into the host-pathogen interaction in the context of single and dual infection, showing remarkable differences in host gene expression modulation by two T. cruzi strains.

bioinformatics↗

bioRxiv2017

Distinct co-expression networks using multi-omic data reveal novel interventional targets in HPV-positive and negative head-and-neck squamous cell cancer

The human papillomavirus (HPV) is present in a significant fraction of head-and-neck squamous cell cancer (HNSCC). However, a comprehensive understanding of disease progression profiles comparing HPV+ and HPV- HNSCC cases is still lacking. The main goal of this study was to identify distinct co-expression patterns between HPV+ and HPV- HNSCC and to provide insights into potential regulatory mechanisms/effects (such as methylation and mutation) within the analyzed networks. For conducting this, we selected 276 samples from The Cancer Genome Atlas database comprising data of gene expression, methylation profiles and mutational patterns, in addition to clinical information (HPV status and tumor staging). We further added external information such as the identification of transcription factors to the networks. Genes were selected as differentially expressed and differentially methylated based on HPV status, of which 12 genes were doubly selected, including SYCP2, GJB6, FLRT3, PITX2 and CCNA1. Weight correlation network analysis was used to identify co-expression modules and a systematic approach was applied to refine them and identify key regulatory elements integrating results from the other omics. Three main modules were associated with distinct co-expression patterns in HPV+ versus HPV- HNSCC. The molecular signatures found were mainly related to cell fate specification, keratinocyte differentiation, focal adhesion and regulation of protein oligomerization. This study provides comprehensive insights into complex genetic and epigenetic particularities in the development and progression of HNSCC in patients according to HPV status, identifying unseen gene interactions, and may contribute to unveiling specific genes/pathways as novel therapeutic targets for HNSCC.

systems biology↗