Biology subjects

Suarez-Bonnet, A.

Publications and source records attributed to Suarez-Bonnet, A..

8 recordsLinked to original sources

bioRxiv2026

Diverse lung challenges elicit a conserved monocyte-to-macrophage differentiation blueprint

Alveolar macrophages (AM) form a first line of defence to lung insults. These insults often lead to replacement of foetal-derived tissue-resident AMs (fAMs) by monocyte-derived AMs (mono-AMs) with different functionality, which impacts lung immunity long-term. However, whether these alterations are conserved or insult-specific is not well understood. Here, we show that respiratory syncytial virus (RSV) infection remodels the AM compartment long-term. We perform comparative analyses of fAMs and mono-AMs after RSV infection, influenza (IAV) infection and clodronate liposome administration to derive rules governing the functional and transcriptional changes in AM across insults. We identify a crucial tissue integration checkpoint of CD11b+ mono-AMs which involves acquisition of proliferative capacity and requires EGR2-mediated transcriptional rewiring. Mono-AMs elicited by RSV, influenza or clodronate liposomes have a hard-wired ontogeny-dependent stereotypical profile of transcription, metabolism and enhanced immunoreactivity despite a substantially different inflammatory environment during differentiation; accordingly, mono-AMs, whether elicited by infection or sterile depletion, protect from subsequent S. pneumoniae infection. By contrast, fAMs are more susceptible to subtle, context-dependent transcriptional alterations. Our findings highlight that long-term changes in the AM compartment show origin-dependent phenotypic divergence and that mono-AM integration follows a hard-wired trajectory fine-tuned by environmental factors.

immunology↗

bioRxiv2026

An injectable soft implant for long-acting, reversible, ultra-stable release of therapeutics

Providing long-term (>6 months) zero-order drug release from easily administered formulations is a key challenge in improving patient adherence and facilitating access. Herein, we report the design and development of an injectable, biodegradable, long-acting polymeric microparticle-embedded hydrogel platform for prolonged, zero-order release of therapeutics. This "soft implant" is injectable for ease of administration and can be retrieved via a small incision, allowing for discontinuation of therapy if desired. Central to the platform are surface-eroding poly(orthoester) (POE) microparticles, which were molecularly tailored to tune zero-order drug release across a wide range of timeframes. We demonstrate the clinical potential of the "soft implant" using levonorgestrel, a contraceptive agent requiring sustained dosing. In vitro, we observed zero-order release for 300 days, projected for >12 months, with behavior consistent with surface erosion further supported through Raman chemical mapping. In vivo studies confirmed zero-order release for six months, projected to 12 months, from a subcutaneous injection in rats. We envision that our platform could transform therapies that require long-term, regular drug dosing, significantly improving compliance and therapy outcomes.

bioengineering↗

bioRxiv2025

The penetrant chordoid glioma PRKCA mutation is an oncogenic gain-of-function kinase inactivation eliciting early onset chondrosarcoma in mice.

The penetrant PRKCA D463H mutation, a biomarker and potential driver in chordoid glioma, was found to provoke the development of chondrosarcomas in heterozygous knock-in mice. This mutation entirely abrogates kinase activity, but strikingly no oncogenic phenotype is observed for the related inactivating mutation D463N indicating that the lack of activity is not the driver. In cells, the D463H mutant closely mirrored PKC WT behaviours and retained ATP binding, contrary to the related D463N mutant. Mechanistically, the PKC D463H mutant protein was found to display quantitative alterations to the PKC interactome, enhancing association with epigenetic regulators. This aligned with transcriptomic changes which resembled an augmented PKC expression program, with enhanced BRD4, Myc and TGF{beta} signatures. D463H dependent reduced sensitivity to the BET inhibitors JQ1 and AZD5153 indicates the functional importance of these pathways. The data show that D463H is a dominant gain-of-function oncogenic mutant, operating through a non-catalytic allosteric mechanism. One Sentence SummaryA PKC catalytic inactivating mutation confers gain-of-function properties - a paradigm shift in kinase actions.

cancer biology↗

bioRxiv2024

Branched actin networks in innate immune cells mediate host microbiota homeostasis.

Assembly of branched actin networks, driven by the Arp2/3 complex are essential for the function and integrity of the immune system. Patients with loss-of-function mutations in the ARPC5 subunit of the Arp2/3 complex develop inflammation and immunodeficiency after birth, leading to early mortality. However, the mechanistic basis for these phenotypes remains obscure. Here we demonstrate that loss of Arpc5 in the murine hematopoietic system, but not the corresponding Arpc5l isoform causes early-onset intestinal inflammation after weaning. This condition is initiated by microbiota breaching the ileal mucosa, leading to local and systemic inflammation. Macrophage and neutrophils infiltrate into the ileum, but in the absence of Arpc5 fail to restrict microbial invasion. Loss of Arpc5 compromises the ability of macrophages to phagocytose and kill intra-cellular bacteria. Our results underscore the indispensable role of Arpc5, but not Arpc5l containing Arp2/3 complexes in mononuclear phagocytes function and host-microbiota homeostasis. One-Sentence SummaryArpc5 containing Arp2/3 complexes are essential for host-microbiota homeostasis

immunology↗

bioRxiv2024

Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells

Several mechanisms of resistance of cancer cells to cyclin-dependent kinase inhibitors (CDKi) have been identified, including the upregulation of metabolic regulators such as glutaminase. However, whether such mechanisms and targets are optimal has not been determined. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDKi selectively targeting CDK4/6, or Telaglenestat, a selective glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenestat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growth in vivo, and Telaglenestat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenestat. In conclusion, combination with Telaglenestat optimally forestalls acquired resistance to Palbociclib in cancer cells.

cancer biology↗

bioRxiv2023

Blimp-1 and c-Maf regulate common and unique gene networks to protect against distinct pathways of pathobiont-induced colitis

Intestinal immune responses to commensals and pathogens are controlled by IL-10 to avoid intestinal immune pathology. We show that the transcription factors Blimp-1 (Prdm-1) and c-Maf are co-dominant regulators of Il10 in Foxp3+ regulatory T cells, but also negatively regulate proinflammatory cytokines in effector T cells. Mice with T cell-specific deletion of Prdm-1, Maf or the combination of both transcription factors did not develop inflammatory intestinal pathologies at the steady state. Double deficient Prdm1fl/flMaffl/flCd4Cre mice infected with Helicobacter hepaticus developed severe colitis with a major increase in TH1/NK/ILC1 effector genes in lamina propria leucocytes (LPLs), while Prdm1fl/flCd4Cre and Maffl/flCd4Cre mice showed mild/moderate pathology and a less-marked Type I effector response. LPLs from infected Maffl/flCd4Cre mice showed increased Il17a expression and an accompanying increase in granulocytes and myeloid cells, which was less marked in Prdm1fl/flMaffl/flCd4Cre mice, with increased T cell-myeloid-neutrophil interactions inferred from scRNA-seq analysis and confirmed by immunofluorescent analysis of colon sections. Genes over-expressed in human IBD showed differential expression in the LPL from infected mice in the absence of Prdm1 or Maf, revealing potential pathobiologic mechanisms of human disease.

immunology↗

bioRxiv2023

Palmitoyl transferase ZDHHC20 promotes pancreatic cancer metastasis

Metastasis is one of the defining features of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor prognosis. In this study, the palmitoyl transferase ZDHHC20 was identified in an in vivo shRNA screen as critical for metastatic outgrowth, with no effect on proliferation and migration in vitro, or primary PDAC growth in mice. This phenotype is abrogated in immunocompromised animals, and in animals with depleted natural killer (NK) cells, indicating that ZDHHC20 affects the interaction of tumour cells and the innate immune system. Using a chemical genetics platform for ZDHHC20-specific substrate profiling, a number of novel substrates of this enzyme were identified. These results describe a role for palmitoylation in enabling distant metastasis that could not have been detected using in vitro screening approaches and identify potential effectors through which ZDHHC20 promotes metastasis of PDAC.

cancer biology↗

bioRxiv2022

USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development

Truncating mutation of the tumor suppressor gene adenomatous polyposis coli (APC) is the hallmark of colorectal cancer (CRC), resulting in constitutive WNT activation. Despite decades of research, targeting WNT signaling in cancer remains challenging due to its essential role in normal stem cell maintenance. We have previously shown that the deubiquitinating enzyme USP7 is a tumor-specific WNT activator in APC-truncated cells by deubiquitinating and stabilizing {beta}-catenin, but its role in gut tumorigenesis is unknown. Here we show in vivo that deletion of Usp7 in Apc-truncated mice inhibits crypt hyperproliferation and intestinal tumor development. Importantly, intestine-specific Usp7 mutation does not yield any phenotype in wildtype animals, indicating that its loss is well tolerated. Unexpectedly, prolonged deletion of Usp7 in Apc+/- intestine induces varying degrees of colitis. Treatment with a USP7 inhibitor suppresses growth of patient-derived cancer organoids in vitro and of xenografts carrying APC truncations. We propose that USP7 inhibition may be efficacious for tumor-specific therapy of sporadic APC-mutated CRC, while patients with germline APC mutations should not receive such treatment. HighlightsO_LIUsp7 deletion in Apc-truncated mice reduces intestinal tumor development. C_LIO_LIIntestine-specific Usp7 mutation mutation has no phenotype in wildtype animals. C_LIO_LITreatment with Usp7 inhibitor suppresses growth of patient-derived cancer organoids carrying Apc truncations in vitro and of xenografts. C_LI

cancer biology↗