Biology subjects

Suarez-Farinas, M.

Publications and source records attributed to Suarez-Farinas, M..

13 recordsLinked to original sources

bioRxiv2026

Platelet-programmed circulating tumor cells signal to monocytes through a candidate CD40LG-ITGA5:ITGB1 myeloid checkpoint axis in breast cancer

Circulating tumor cells (CTCs) are key drivers of distant metastasis, while platelets facilitate this process by protecting them from immune surveillance. However, the detection of CTCs exhibiting platelet markers and their communication with monocytes has not been thoroughly investigated. This study seeks to identify the intercellular communication of CTCs that have acquired platelet traits by integrating single-cell RNA-seq data of 377 CTCs and 2,634 white blood cells. Trajectory analysis identified a subpopulation of CTCs with enhanced platelet-related functions, including platelet aggregation and resistance to NK cell-mediated cytotoxicity, termed Platelet-Programmed CTCs. The Dampened Weighted Least Squares method was implemented to estimate the platelet-programmed tumor cell proportion in 1,102 bulk RNA-seq samples from primary breast cancer tumors. A strong inverse association was found between platelet-programmed tumor cell proportion and overall survival (Cox-PH p-value =0.00419, HR=6 per 10% increase in proportion, 95% CI:1.76-20.7). However, this association did not differ significantly between early- and late-stage patients. Cell-cell communication analyses and molecular docking revealed the CD40LG-ITGA5:ITGB1 pair as a potential immune checkpoint candidate for monocytes in cancer (Hex score=-656.83; TNF-TNFR reference complex=-515). However, further experimental and clinical validation is required to translate these findings. In conclusion, these findings deepen our understanding of the immune evasion mechanisms of CTCs by acquiring platelet characteristics. This immune checkpoint axis offers a novel avenue for further experimental validation and future intervention.

cancer biology↗

bioRxiv2024

Rigosertib reverses hypertrophic cardiomyopathy in RAF1-associated Noonan syndrome

BackgroundRASopathies constitute a group of rare genetic disorders caused by mutations in genes that reside along the canonical Ras/MAPK signaling pathway, affecting cell growth and differentiation. These syndromes, which include conditions like Noonan syndrome (NS), are characterized by developmental delays, distinctive facial dysmorphia, and a variety of cardiac defects, notably hypertrophic cardiomyopathy (HCM). Despite their prevalence and impact, therapeutic options for RASopathies remain limited. Rigosertib, a novel dual Ras/MAPK and PI3K/AKT pathway inhibitor, is currently in clinical trials for treatment of melanoma and recessive dystrophic epidermolysis bullosa. Here, we identify rigosertib as a candidate therapy for RAF1-associated HCM. Methods and ResultsOur Drosophila screen of clinically relevant drugs and compounds identified rigosertib as broadly effective across a panel of transgenic RASopathy fly transgenic models, indicating that rigosertib may be effective against multiple disease isoforms. Analysis of a Drosophila model targeting a RAF1L613V transgene to the heart found that rigosertib reduced aspects of cardiac hypertrophy. Rigosertib treatment prevented or regressed cellular hypertrophy in human induced pluripotent stem cell-(iPSC-) derived cardiomyocytes homozygous for the NS-associated RAF1S257L allele. We extended these findings to a mammalian model, using Raf1L613V/+ KI mice to explore the therapeutic implications of rigosertib on RAF1-driven HCM. Longitudinal six-week treatment with rigosertib in these mice resulted in significant improvement in left ventricular chamber dimension and posterior wall thickness, total heart mass, size of individual cardiomyocytes (CMs), as well as reversal of cardiac hypertrophy. Rigosertib treatment also led to normalized fetal gene expression and inhibition of ERK and AKT pathway activities in primary CMs isolated from Raf1L613V/+ mice. Cardiac function, as assessed by echocardiography, showed significant improvement in ejection fraction and fractional shortening, with molecular studies confirming downregulation of hypertrophic markers and signaling pathways. Together with the Drosophila data, these mammalian results support the potential and use for rigosertib to reverse pathological hypertrophy in NS through targeted pathway inhibition in patients. Moreover, in addition to its effects in the heart, rigosertib treatment in mice also significantly improved other NS-associated syndromic features, including increasing bone growth and correcting craniofacial abnormalities. ConclusionsTaken together, our findings suggest rigosertib effectively normalizes and reverses RASopathy-associated HCM as well as other NS-associated syndromic features, supporting its potential for development as a promising treatment for RAF1-associated HCM and, potentially, other RASopathies-dependent pathologies. This study not only highlights the therapeutic potential of rigosertib but also demonstrates the utility of an integrated approach using Drosophila, iPSC and mammalian models to elucidate drug effects across complex biological systems.

molecular biology↗

bioRxiv2024

HIV-1 infection is associated with depletion of germinal center B cells and a decrease in IgA+ plasma cells in the GI tract

Gastrointestinal (GI) B cells and plasma cells (PCs) are critical to mucosal homeostasis and the host response to HIV-1 infection. Here, high resolution mapping of human B cells and PCs sampled from the colon and ileum during both viremic and suppressed HIV-1 infection identified a reduction in germinal center (GC) B cells and follicular dendritic cells (FDCs) during HIV-1 viremia. IgA+ PCs are the major cellular output of intestinal GCs and were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling, persisted in antiretroviral therapy (ART)-treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations were associated with changes in the intestinal microbiome composition and systemic inflammation. These findings highlight a key immune defect in the GI mucosa due to HIV-1 viremia. One Sentence SummaryIntestinal germinal center B cell reduction in HIV-1 infection linked to reduced IgA+ plasma cells and systemic inflammation.

immunology↗

bioRxiv2023

Myeloid cell influx into the colonic epithelium is associated with disease severity and non-response to anti-Tumor Necrosis Factor Therapy in patients with Ulcerative Colitis.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC. Prominently, reduced frequencies of mature BEST4+OTOP2+ absorptive and BEST2+WFDC2+ secretory epithelial enterocytes were associated with the replacement of homeostatic, resident TRDC+KLRD1+HOPX+ {gamma}{delta}+ T cells with RORA+CCL20+S100A4+ TH17 cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified by S100A8, HIF1A, TREM1, CXCR1) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649). Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.

immunology↗

bioRxiv2023

Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis

Targeting the 4{beta}7-MAdCAM-1 axis with vedolizumab (VDZ) is a front-line therapeutic paradigm in ulcerative colitis (UC). However, mechanism(s) of action (MOA) of VDZ remain relatively undefined. Here, we examined three distinct cohorts of patients with UC (n=83, n=60, and n=21), to determine the effect of VDZ on the mucosal and peripheral immune system. Transcriptomic studies with protein level validation were used to study drug MOA using conventional and transgenic murine models. We found a significant decrease in colonic and ileal naive B and T cells and circulating gut-homing plasmablasts ({beta}7+) in VDZ-treated patients, pointing to gut-associated lymphoid tissue (GALT) targeting by VDZ. Murine Peyers patches (PP) demonstrated a significant loss cellularity associated with reduction in follicular B cells, including a unique population of epithelium-associated B cells, following anti-4{beta}7 antibody (mAb) administration. Photoconvertible (KikGR) mice unequivocally demonstrated impaired cellular entry into PPs in anti-4{beta}7 mAb treated mice. In VDZ-treated, but not anti-tumor necrosis factor-treated UC patients, lymphoid aggregate size was significantly reduced in treatment responders compared to non-responders, with an independent validation cohort further confirming these data. GALT targeting represents a novel MOA of 4{beta}7-targeted therapies, with major implications for this therapeutic paradigm in UC, and for the development of new therapeutic strategies.

immunology↗

bioRxiv2022

Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses

Systems biology approaches have been used to define molecular signatures and mechanisms of immunity to vaccination. However, most such studies have been done with single vaccines, and comparative analysis of the response to different vaccines is lacking. We integrated temporal transcriptional data of over 3,000 samples, obtained from 820 healthy adults across 28 studies of 13 different vaccines and analyzed vaccination-induced signatures associated with the antibody response. Most vaccines induced similar kinetics of shared transcriptional signatures, including signatures of innate immunity occurring 1-3 days post-vaccination, as well as the canonical plasmablast and cell cycle signatures appearing 7 days post-vaccination. However, the yellow fever vaccine YF-17D uniquely induced an early transient signature of T and B cell activation at Day 1, followed by delayed antiviral/interferon and plasmablast signatures that peaked at Days 7 and 14-21, respectively. Thus, despite the shared transcriptional response to most vaccines, at any given time point there was no evidence for a "universal signature" that could be used to predict the antibody response to all vaccines. However, accounting for the asynchronous nature of responses led to the identification of a time-adjusted signature that improved prediction antibody of responses across vaccines. These results provide a transcriptional atlas of the human immune response to vaccination and define a common, time-adjusted signature of antibody responses to vaccination.

immunology↗

bioRxiv2021

The Immune Signatures Data Resource: A compendium of systems vaccinology datasets

Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines, including those targeting seasonal influenza, yellow fever, and hepatitis B. These data are made available to the broader scientific community through the ImmuneSpace data portal and analysis engine leveraging the NIH/NIAID ImmPort repository1,2. However, a barrier to progress in this area is that comparative analyses have been limited by the distributed nature of some data, potential batch effects across studies, and the absence of multiple relevant studies from non-HIPC groups in ImmPort. To support comparative analyses across different vaccines, we have created the Immune Signatures Data Resource, a compendium of standardized systems vaccinology datasets. This data resource is available through ImmuneSpace, along with code to reproduce the processing and batch normalization starting from the underlying study data in ImmPort and the Gene Expression Omnibus (GEO). The current release comprises 1405 participants from 53 cohorts profiling the response to 24 different vaccines and includes transcriptional profiles and antibody response measurements. This novel systems vaccinology data release represents a valuable resource for comparative and meta-analyses that will accelerate our understanding of mechanisms underlying vaccine responses. [Table 1]

systems biology↗

bioRxiv2021

An innate immune activation state prior to vaccination predicts responsiveness to multiple vaccines

Many factors determine whether an individual responding to vaccination will generate an immune response that can lead to protection. Several studies have shown that the pre-vaccination immune state is associated with the antibody response to vaccines. However, the generalizability and mechanisms that underlie this association remain poorly defined. Here, we sought to identify a common pre-vaccination signature and mechanisms that could predict the immune response across a wide variety of vaccines. We leveraged the "Immune Signatures Data Resource" created by the NIH Human Immunology Project Consortium (HIPC) to integrate data from 28 studies involving 13 different vaccines and associate the blood transcriptional status of 820 healthy young adults with their responses. An unsupervised analysis of blood transcriptional profiles across studies revealed three distinct pre-vaccination states, characterized by the differential expression of genes associated with a pro-inflammatory response, cell proliferation, and metabolism alterations downstream of NF{kappa}B and IRF7. Innate and adaptive immune cell subset-specific genes were also associated with the three pre-vaccination states. Importantly, individuals whose pre-vaccination state was enriched in pro-inflammatory response genes known to be downstream of NF{kappa}B tended to have higher serum antibody responses one month after vaccination. A supervised analysis of the same data resulted in a single classifier, also enriched for NF{kappa}B regulated genes, that predicted the antibody response across most of the vaccines. Projection into single-cell RNA-sequencing data suggested that this pre-vaccination state was attributable to the signature of activation of non-classical monocytes and myeloid dendritic cells. Transcriptional signatures of acute responses to bacterial and not viral infections were enriched in the high pro-inflammatory pre-vaccination state and also included NF{kappa}B regulated genes. The pro-inflammatory pre-vaccination state was highly reminiscent of the innate activation state triggered by TLR ligands or adjuvants. These results demonstrate that wide variations in the transcriptional state of the immune system in humans can be a key determinant of responsiveness to vaccination. They also define a transcriptional signature NF{kappa}B activation at baseline, that is associated with a greater magnitude of antibody response to multiple vaccines, and suggest that modulation of the innate immune system by next-generation adjuvants targeting NF{kappa}B before vaccine administration may improve vaccine responsiveness.

systems biology↗

bioRxiv2021

Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of ulcerative colitis (UC) patients require colectomy within five years of diagnosis, but polygenic risk scores (PRS) utilizing findings from GWAS are unable to provide meaningful prediction of this adverse status. By contrast, in Crohns disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a Transcriptional Risk Score (TRS). Here we demonstrate that both measured (TRS) and polygenic predicted gene expression (PPTRS) identify UC patients at 5-fold elevated risk of colectomy with data from the PROTECT clinical trial and UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with transcriptome-wide association studies to stratify risk of disease complications.

genetics↗

bioRxiv2020

Dietary restriction in the long-chain acyl-CoA dehydrogenase knockout mouse

Patients with a disorder of mitochondrial long-chain fatty acid {beta}-oxidation (FAO) have reduced fasting tolerance and may present with hypoketotic hypoglycemia, hepatomegaly, (cardio)myopathy and rhabdomyolysis. Patients should avoid a catabolic state because it increases reliance on FAO as energy source. It is currently unclear whether weight loss through a reduction of caloric intake is safe in patients with a FAO disorder. We used the long-chain acyl-CoA dehydrogenase knockout (LCAD KO) mouse model to study the impact of dietary restriction (DR) on the plasma metabolite profile and cardiac function. For this, LCAD KO and wild type (WT) mice were subjected to DR (70% of ad libitum chow intake) for 4 weeks and compared to ad libitum chow fed mice. We found that DR had a relatively small impact on the plasma metabolite profile of WT and LCAD KO mice. Echocardiography revealed a small decrease in left ventricular systolic function of LCAD KO mice, which was most noticeable after DR, but there was no evidence of DR-induced cardiac remodeling. Our results suggest that weight loss through DR does not have acute and detrimental consequences in a mouse model for FAO disorders.

physiology↗

bioRxiv2020

Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2 related disease

The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) replication within enterocytes. Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation and IBD treatment. A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and non-biologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. Additionally, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19.

immunology↗

bioRxiv2018

Gut microbiota density influences host physiology and is shaped by host and microbial factors

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohns disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.

microbiology↗

bioRxiv2018

Microbial Engraftment and Efficacy of Fecal Microbiota Transplant for Clostridium difficile Patients With and Without IBD

Background & AimsRecurrent and refractory Clostridium difficile infections (CDI) are effectively treated with fecal microbiota transplant (FMT). Uncertainty exists regarding the effectiveness of FMT for CDI with underlying inflammatory bowel disease (IBD), its effects on disease activity and its effectiveness transferring the donor microbiome to patients with and without IBD. This study aims to determine FMTs effectiveness in subjects with and without IBD, its impact on IBD activity, the level of microbiome engraftment, and predictors of CDI recurrence.\n\nMethodsSubjects with and without IBD who underwent FMT for recurrent or refractory CDI between 2013 and 2016 at The Mount Sinai Hospital were followed for up to 6 months. The primary outcome was CDI recurrence 6 months after FMT. Secondary outcomes were (1) CDI recurrence 2 months after FMT; (2) Frequency of IBD flare after FMT; (3) Microbiome engraftment after FMT; (4) Predictors of CDI recurrence.\n\nResultsOverall, 134 patients, 46 with IBD, were treated with FMT. There was no difference in recurrence in patients with and without IBD at 2 months (22.5% vs 17.9%; p=0.63) and 6 months (38.7% vs 36.5%; p>0.99). Proton pump inhibitor use, severe CDI, and comorbid conditions were predictors of recurrence. The pre-FMT microbiome was not predictive of CDI recurrence. Subjects with active disease requiring medication escalation had reduced engraftment. There was no difference in engraftment based on IBD endoscopic severity at FMT.\n\nConclusionsIBD did not affect CDI recurrence rates 6 months after FMT. Pre-FMT microbiome was not predictive of recurrence, and microbial engraftment was dependent on IBD treatment escalation but not on underlying disease severity.

microbiology↗