Biology subjects

Villalba, M.

Publications and source records attributed to Villalba, M..

6 recordsLinked to original sources

bioRxiv2025

Metabolic rewiring of cancer cells induces metastasis via ERK5 but triggers recognition by NK cells

Metastasis is largely controlled by Natural Killer (NK) cell-mediated immune surveillance. To colonize new environments, cancer cells undergo epithelial to mesenchymal transition (EMT), which allows them to detach and migrate. EMT is fueled by fatty acid oxidation (FAO), which partially replaces glycolytic-based tumor metabolism. Whether metabolic rewiring affects the targeting of cancer cells by NK cells remains unknown. Here, we show that forcing solid cancer cells to perform FAO by inhibiting pyruvate dehydrogenase kinase 1 with dichloroacetate (DCA) activates extracellular signal-regulated kinase-5 (ERK5), triggering EMT and tumor cell migration and invasion. Concomitantly, FAO induces the expression of ligands that mediate NK cell recognition. Consequently, NK cells better infiltrated DCA-treated 3D tumor spheroids, where they exerted their cytotoxic effects. DCA-treated cells showed increased migration in a zebrafish model, whereas metastasis from mammary cancer cells grafted into immune-deficient mice was enhanced by DCA. These migrating/metastatic cells are preferentially killed by NK cells, which strongly limit their invasive potential. Hence, FAO promotes both metastasis and NK-mediated tumor surveillance, highlighting the Achilles heel of metastatic cells, which may offer new therapeutic opportunities. TeaserMetastasis recognition and killing by immune cells, such as NK cells, requires a metabolic shift that relies on lipid metabolism.

cancer biology↗

bioRxiv2025

Using Monoids for the Integration of Genomic and Metabolic Parameters in the Prediction of Phenotypes in Regulatory Cascades.

Molecular network modeling requires the use of mathematical and computational formalisms for a robust and accurate prediction of phenotypes. Furthermore, there is a need to extend these formalisms to be applied to large-scale molecular networks, thus helping in the understanding of biological complexity. In this work, we propose an extension to the modeling framework known as design principles, developed by M.A. Savageau, which is based on the Power Law Modeling. While valuable to understand several properties of molecular networks, the power law modeling cannot be used to infer kinetic orders, which are typically related to the number of binding sites present in molecules. We modified the traditional approach by incorporating the use of monoids generating a new methodological approach that we call Genotype Arithmetic. This approach solves local geometry, solving networks through monoids and varieties, reducing the computational complexity. The resulting combinatorial object contains a family of geometric points, whose fixed points in the exponent space define a set of constraints determining the correct kinetic order to be used in the power law modeling. This characteristic constitutes a prediction of the binding strength and/or the number of DNA binding sites in regulatory sequences, as well as the reaction orders in enzymatic kinetics. To show the applicability of the present approach, we show how the number of binding sites can be approximated in metabolic pathways formed by 3 to 9 reactions, in allosteric systems of end-product inhibition with intermediate catalytic reactions and one gene inhibition. Author summaryIn this work, was revised the Power Law Modeling to analyze and predict kinetic and genomic parameters in molecular networks. It was developed a new approach, called Genotype Arithmetic, which takes advantage from the properties of Monoids found within this formalism. Using this algebraic and geometric technique, were predicted the number of binding sites for various cases associated with the pathway length in the gene allosteric system for end-product inhibition.

bioinformatics↗

bioRxiv2024

mRNA-delivered consensus allergens induce a neutralizing IgG response against food and pollen allergens

Pollen-food allergy syndrome (PFAS) affects a significant proportion of the global population with a major health and socioeconomic impact. Patients are generally treated against the major sensitized allergen which does not warrant protection against cross-reactive allergens, leading to long and ineffective treatment regimens. For food allergies, patient guidelines rely on source avoidance, leading to dietary restrictions and reduced quality of life - in particular for those suffering from PFAS. To overcome these limitations, we introduce a novel allergy immunotherapy (AIT) approach utilizing consensus allergens and mRNA technology to achieve broader, safer, and faster desensitization in PFAS patients. We first designed a consensus allergen of orthologs of non-specific Lipid Transfer Proteins (cnsLTP-1) representing a broad spectrum of nsLTP allergens prevalent in food and pollen sources. CnsLTP-1 was delivered to naive BALB/c mice using mRNA-lipid nanoparticles (mRNA-LNP) as vehicle, or by a traditional protein formulation, to assess if it elicits broad protection against allergens from different sources. Immunization with both mRNA-LNP and protein formulations demonstrated that cnsLTP-1-specific IgGs could be induced, whilst the mRNA-LNP formulation notably avoided the induction of allergen-specific IgEs. The induced antibodies were capable of recognizing and binding to a variety of nsLTPs, and effectively blocked the binding of allergens by allergic patient serum IgEs. This study thus demonstrates that the presented AIT strategy, based on mRNA-LNP technology and consensus allergens, could find clinical utility by addressing the limitations of current AIT. Further development of this technology platform could pave the way for more effective and patient-friendly treatments for PFAS and other cross-reactive allergies.

bioengineering↗

bioRxiv2024

The SUMOylation inhibitor TAK-981 (Subasumstat) triggers IFN-I-dependent activation of Natural Killer cells against Acute Myeloid Leukemias.

Natural Killer (NK) cells play a pivotal role in mounting an anti-cancer immune response. Patients with diminished NK cells number and activity face less favorable prognosis. Promising therapeutic strategies include the adoptive transfer of NK cells or the reactivation of patients own NK cells. TAK-981, a first-in-class inhibitor of SUMOylation undergoing phase I/II clinical trials for cancer, is emerging as an immunomodulatory drug. Here, we demonstrate that TAK-981 activates NK cells from healthy donors and patients with Acute Myeloid Leukemia (AML), a cancer with very poor prognosis. TAK-981 heightens their degranulation capacity, secretion of inflammatory cytokines (IFN-{gamma}, TNF-, FasL), and cytotoxicity against AML cells. In vivo, TAK-981 also enhances the anti-leukemic activity of ex-vivo expanded human NK cells. At the molecular level, TAK-981 first induces IFNB1 gene in NK cells, leading to the secretion of type I Interferon (IFN-I), which binds to the Interferon receptor IFNAR. This induces Interferon-Stimulated Genes (ISG) and activates NK cells in vitro and in vivo. Finally, TAK-981 stimulates IFN-I secretion by monocytes, which contributes to the activation of NK cells in trans. Altogether, targeting SUMOylation could be a promising strategy to reactivate AML patients NK cells and enhance the efficiency of NK cells-based therapies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/580882v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1a5fd47org.highwire.dtl.DTLVardef@974336org.highwire.dtl.DTLVardef@bdb99dorg.highwire.dtl.DTLVardef@1e4fe15_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

NK cells acquire CCR5 and CXCR4 by trogocytosis in people living with HIV-1

NK cells play a major role in the antiviral immune response, including against HIV-1. HIV patients have impaired NK cell activity with decrease in CD56dim NK cells and increase in CD56-CD16+ subset and recently it has been proposed that a population of CD56+NKG2C+KIR+CD57+ cells represents antiviral memory NK cells. Antiretroviral therapy (ART) partly restores the functional activity of this lymphocyte lineage. NK cells when interacting with their targets can gain antigens from them by the process of trogocytosis. Here we show that NK cells can obtain CCR5 and CXCR4, but barely CD4, from T cell lines by trogocytosis in vitro. By UMAP (Uniform Manifold Approximation and Projection), we show that aviremic HIV patients have unique NK cell clusters that encompass for cells expressing CCR5, NKG2C and KIRs, but lack CD57 expression. Viremic patients have a larger proportion of CXCR4+ and CCR5+ NK cells than healthy donors (HD) and this is largely increased in CD107+ cells, suggesting a link between degranulation and trogocytosis. In agreement, UMAP identified a specific NK cell cluster in viremic HIV patients, which contains most of the CD107a+, CCR5+ and CXCR4+ cells. However, this cluster lacks NKG2C expression. Therefore, NK cells can gain CCR5 and CXCR4 by trogocytosis, which depends on degranulation. Author SummaryNK cells play a major role in the antiviral immune response, including against HIV-1. HIV-1 infection largely impacts NK cell lineage. However, identification of the NK cells fighting the virus and eliminating infected cells has remained elusive. By using FACs analysis and analyzing T cell markers, we identify specific NK cell subsets that have gained T cell antigen markers by trogocytosis. We show a strong association of degranulation and trogocytosis ex vivo suggesting that NK cells are eliminating or trying to eliminate HIV-1 infected cells. Moreover, we show that NK cells can obtain the HIV-1 coreceptors CCR5 and CXCR4, but barely CD4, from T cells. Therefore, by uncovering that NK cells gain CCR5 and CXCR4 by trogocytosis we show that NK cells are actively fighting against HIV-1 infection in viremic and aviremic patients. This should help to identify why certain patients better control the virus, to develop new anti-HIV-1, NK cell-based, immunotherapies and to understand if NK cells can be a new HIV-1 reservoir.

immunology↗

bioRxiv2019

Ki-67 supports global gene expression programmes driving tumourigenesis

Recent studies have shown that the cell proliferation antigen Ki-67 is not required for cell proliferation. Here, we demonstrate that Ki-67 enables implementation of transcriptional programmes conferring cellular plasticity, and is required for each step of tumour initiation, growth and metastasis. Ki-67 knockout causes global transcriptome remodelling, which, in mammary carcinoma cells, inhibits the epithelial-mesenchymal transition in a polycomb-repressive complex 2-dependent manner. This results in suppression of stem cell characteristics and sensitisation to various drug classes. Cancer cells lacking Ki-67 proliferate normally in vivo, but tumour growth is inhibited due to disrupted angiogenesis, and metastasis is abrogated. Finally, mice lacking Ki-67 are resistant to chemical or genetic induction of intestinal tumourigenesis. Thus, Ki-67, which is expressed in all proliferating cancer cells, confers the plasticity required for different steps of carcinogenesis.

cancer biology↗