Biology subjects

Carrasco Pro, S.

Publications and source records attributed to Carrasco Pro, S..

5 recordsLinked to original sources

bioRxiv2025

Pan-cancer analysis in the real-world setting uncovers immunogenomic drivers of acquired resistance post-immunotherapy

Immune checkpoint blockade (ICB) has revolutionised cancer therapy, yet resistance -- both primary and acquired -- remains a significant obstacle, affecting the majority of patients. Here, we leveraged a large-scale, real-world clinicogenomic dataset to systematically explore the molecular underpinnings of ICB resistance in the post-progression setting. Analysing over 5,000 pan-cancer patients with clinical and pre-/post-treatment genomic and transcriptomic data, we identify distinct immunogenomic drivers of acquired vs. primary ICB resistance. Post-ICB progression, acquired resistance showed extended survival compared to primary resistance across all cancer types. The acquired resistance clinical phenotype was paralleled by a universally immune-inflamed, albeit dysfunctional, tumour microenvironment (TME) at the onset of acquired resistance, with sustained or ICB-induced inflammatory and interferon responses. We confirm previously described mechanisms of acquired resistance, including B2M loss-of-function (LoF) in non-small cell lung cancer (NSCLC), and identify novel potential mediators, including LoF of TGFBR2 in NSCLC, CYLD in head and neck cancer, and RUNX1 in triple negative breast cancer. Further supporting their involvement in resistance, these acquired ICB alterations associated with immune-escaped TMEs, characterised by active immunomodulatory oncogenic signalling, hyperproliferation and invasiveness, or altered tumour metabolism. These findings emphasise the heterogeneity of molecular drivers of acquired resistance to ICB within and across cancers, and highlight the potential for personalised therapeutic interventions post-progression to improve patient outcomes.

cancer biology↗

bioRxiv2020

Comprehensive mapping of the human cytokine gene regulatory network

Proper cytokine gene expression is essential in development, homeostasis, and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we use enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1,380 interactions between 265 TFs and 108 cytokine gene promoters, greatly expanding the known repertoire of TF-cytokine gene interactions. We found an enrichment of nuclear receptors and confirmed their role in cytokine regulation in primary macrophages. Additionally, we used the eY1H-derived network as a framework to identify pairs of TFs that synergistically modulate cytokine gene expression, and to identify novel TF-cytokine regulatory axes in immune diseases and immune cell lineage development. Overall, the eY1H data provides a rich resource to study cytokine regulation in a variety of physiological and disease contexts.

immunology↗

bioRxiv2018

Uncovering human transcription factor interactions associated with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays

Identifying transcription factor (TF) binding to noncoding variants, uncharacterized DNA motifs, and repetitive genomic elements has been technically and computationally challenging. Current experimental methods, such as chromatin immunoprecipitation, generally test one TF at a time, and computational motif algorithms often lead to false positive and negative predictions. To address these limitations, we developed two approaches based on enhanced yeast one-hybrid assays. The first approach interrogates the binding of >1,000 human TFs to repetitive DNA elements, while the second evaluates TF binding to single nucleotide variants, short insertions and deletions (indels), and novel DNA motifs. Using the first approach, we detected the binding of 75 TFs, including several nuclear hormone receptors and ETS factors, to the highly repetitive Alu elements. Using the second approach, we identified cancer-associated changes in TF binding, including gain of interactions involving ETS TFs and loss of interactions involving KLF TFs to different mutations in the TERT promoter, and gain of a MYB interaction with an 18 bp indel in the TAL1 super-enhancer. Additionally, we identified the TFs that bind to three uncharacterized DNA motifs identified in DNase footprinting assays. We anticipate that these approaches will expand our capabilities to study genetic variation and under-characterized genomic regions.

genomics↗

bioRxiv2018

Interactive single cell RNA-Seq analysis with the Single Cell Toolkit (SCTK)

Single cell RNA-sequencing (scRNA-Seq) allows researchers to profile transcriptional activity in individual cells. However, the complex nature of these data and variability in study design and data generation requires sophisticated computational tools and informed analytical decisions. Here, we present the Single Cell Toolkit (SCTK), an interactive scRNA-Seq analysis package that enables users to perform scRNA-Seq analysis interactively using a command-line workflow or a graphical user interface (GUI) written in R/Shiny.

bioinformatics↗

bioRxiv2018

Global landscape of mouse and human cytokine transcriptional regulation

Cytokines play a central role in immune development, pathogen responses, and diseases. Cytokines are highly regulated at the transcriptional level by combinations of transcription factors (TFs) that recruit cofactors and the transcriptional machinery. Here, we review three decades of studies to generate a comprehensive database reporting 843 and 647 interactions between TFs and cytokines genes, in human and mouse respectively (http://cytreg.bu.edu). We provide a historic perspective on cytokine regulation discussing research trends and biases. More importantly, by integrating this comprehensive database with other functional datasets, we determine general principles governing the transcriptional regulation of cytokine genes. In particular, we show a correlation between TF connectivity and immune phenotype and disease, we discuss the balance between tissue-specific and pathogen-activated TFs regulating each cytokine gene, and cooperativity and plasticity in cytokine regulation. Finally, we illustrate the use of our database as a blueprint to study TF-cytokine regulatory axes in autoimmune diseases.

immunology↗