Biology subjects

Curtis, J.

Publications and source records attributed to Curtis, J..

6 recordsLinked to original sources

bioRxiv2026

Genetic dissection of DNA damage response pathways reveals divergent modulation of PD-1 blockade response in colorectal cancer

Although MSI-H/dMMR colorectal cancers and the rarer subset with pathogenic POLE exonuclease domain mutations can benefit from immune checkpoint blockade, MSS colorectal cancer remains largely refractory, raising the question of whether other DNA damage response defects may also confer sensitivity to immunotherapy. Here, we performed a systematic in vivo screen of recurrently altered DNA damage response (DDR) genes to determine whether distinct repair defects modulate response to PD-1 blockade in MSS colorectal cancer. Using a genome-edited murine model in immunocompetent mice, we found that DDR perturbations produced heterogeneous outcomes, indicating that the immunologic consequences of DNA repair deficiency may be pathway-specific. Loss of Brca1, Brca2, Atm, and Fanca enhanced response to anti-PD-1 therapy, whereas Atr and Msh6 deficiency were associated with poor benefit. Brca1/2-deficient tumors showed the strongest regressions, supporting a link between core homologous recombination deficiency and increased immune sensitivity. In an independent cohort of colorectal cancer patients treated with ICB from the MSK-IMPACT Clinical Sequencing Cohort, BRCA1 alterations were associated with improved survival status, while FANCA alterations showed a similar trend. Because ATM is therapeutically targetable, we evaluated pharmacologic ATM inhibition in MSS colorectal cancer. Sustained ATM inhibition induced immune-related transcriptional programs in vitro and, when administered as a pre-treatment in vivo, enhanced the antitumor activity of PD-1 blockade. Together, these findings suggest that selected DDR alterations may represent candidate biomarkers of immunotherapy sensitivity, while ATM inhibition may provide a rational combination strategy to enhance PD-1 blockade in MSS colorectal cancer.

cancer biology↗

bioRxiv2026

Paralemmin 2 is a shared, alternatively-spliced regulator of axon initial segments and paranodal junctions in oligodendrocytes

Nervous system function depends on highly specialized axonal membrane domains. For example, axon initial segments (AIS), nodes of Ranvier, and paranodal junctions are essential for action potential initia-tion and saltatory conduction. These domains use shared molecular machinery converging on the master scaffolding protein AnkyrinG (AnkG). Using endogenous AnkG-TurboID proximity proteomics, we identify Paralemmin 2 (Palm2), a previously uncharacterized CNS protein, as a shared component of the AIS and nodes of Ranvier in neurons, and paranodes in oligodendrocytes. Palm2 localizes transiently to the AIS and nodes during development, but is found at paranodes throughout life, reflecting cell type-specific splicing of a lipid-modified domain both necessary and sufficient for AnkG interaction. Mice lacking oli-godendroglial Palm2 assemble normal paranodes during development, but aged mice lose paranode in-tegrity due to loss of paranodal AnkG and Neurofascin-155. Our findings identify Palm2 as a lipid raft-associated regulator of axonal and oligodendroglial membrane domains and reveal cell type-specific pro-tein variants as a recurring principle for specializing axonal and glial membrane architectures.

neuroscience↗

bioRxiv2026

Quantitative imaging of schwannoma captures heterogeneity and accelerates preclinical testing, revealing distinct impacts of targeted therapies

Schwannomas are debilitating hallmarks of familial schwannomatoses and common sporadic tumors that form on spinal and cranial nerves. Drug-based therapies for schwannoma are desperately needed but their development has been extremely slow and disappointing, impeded particularly by the poorly understood and surprisingly complex and heterogeneous biology of schwannomas, and by the inefficient use of physiologically relevant in vivo preclinical models. We have addressed these gaps by developing a quantitative imaging-centered workflow that allows both a deep analysis of schwannoma development and accelerated preclinical testing in a widely used genetically engineered mouse model of neurofibromatosis type 2-related schwannomatosis (NF2-SWN). We deployed our workflow to study schwannoma development and to test two clinically relevant drugs (rapamycin and brigatinib) head-to-head. Our results uncovered the very early onset of heterogeneity and macrophage recruitment to initiating schwannomas, and the unexpectedly distinct impacts of the two drugs on both, highlighting the value of the pipeline for rapid, innovative future drug-testing.

cancer biology↗

bioRxiv2025

OASIS: in vivo AAV-mediated transduction and genome editing of adult oligodendrocytes

New viral approaches have revolutionized neuroscience by precisely delivering genes in neurons; for example, to control or monitor activity in specific neuronal cell types. In contrast, the manipulation of oligodendrocytes requires the Cre-LoxP system and gene-by-gene engineering, breeding, and genotyping. Here we introduce OASIS (Oligodendrocyte AAV-CRISPR mediated Specific In vivo editing System), a versatile platform that combines SELECTIV, an AAV-receptor-based transduction strategy, with HiUGE, an NHEJ-mediated CRISPR/Cas9 knock-in approach. We show efficient and specific oligodendrocyte transduction across the brain and tagging of endogenous cytoskeletal, myelin, cell adhesion, scaffolding, and junctional proteins. OASIS enables sparse yet reliable labeling, allowing direct visualization of a proteins subcellular localization with single-cell resolution. We successfully fused the biotin-ligase TurboID with endogenous oligodendroglial Neurofascin-155, thereby achieving targeted biotinylation of the axoglial junction. OASIS is rapidly customizable for any gene-of-interest. Together, OASIS overcomes longstanding barriers in oligodendrocyte biology, providing a powerful system for precise, customizable genome editing and subcellular visualization in the adult brain.

neuroscience↗

bioRxiv2022

HIGHLY PHAGOCYTIC LIPID-ASSOCIATED MACROPHAGES (LAMs) ARE INCREASED IN COLONIC LAMINA PROPRIA IN OBESITY

Little is known about the effects of high fat diet (HFD)-induced obesity on resident colonic lamina propria (LP) macrophages (LPMs) function and metabolism. Here, we report that obesity and diabetes resulted in increased macrophage infiltration in the colon. These macrophages exhibited the residency phenotype CX3CR1hiMHCIIhi, and were CD4-TIM4-. During HFD, resident colonic LPM exhibited a lipid metabolism gene expression signature that overlapped that used to define lipid associated macrophages (LAMs). Via single cell RNA sequencing, we identified a sub-cluster of macrophages, increased in HDF, that were responsible for the LAM signature. Compared to other macrophages in the colon, these cells were characterized by elevated glycolysis, phagocytosis and efferocytosis signatures. CX3CR1hiMHCIIhi colonic resident LPMs had fewer lipid droplets (LD) and decreased triacylglycerol (TAG) content compared to equivalent cells in lean mice, and exhibited increased phagocytic capacity, suggesting that HFD induces adaptive responses in LPMs to limit bacterial translocation.

immunology↗

bioRxiv2022

Genetic Regulators of Sputum Mucin Concentration and Their Associations with COPD Phenotypes

Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n=708 for total mucin, n=215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n=822-1300). Replication analysis was conducted using data from COPDGene (n =5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10-1.80) as well as AE ascertained over three years of follow up (OR=1.41; 95% CI: 1.02-1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB. Author SummaryChronic obstructive pulmonary disease (COPD) is characterized by presence of emphysema and/or chronic bronchitis. Excessive mucus production is a defining phenotype of chronic bronchitis, and is associated with several important features of COPD, including exacerbations and loss of lung function. Recent studies have demonstrated that the amount of mucus produced in COPD patients is an important marker of disease state. We investigated whether common genetic variants are associated with the concentration of two key proteins in mucus, MUC5AC and MUC5B, and whether the variants we identified are also associated with COPD outcomes. We identified multiple genetic variants that were associated with MUC5AC or MUC5B concentration. The strongest association we detected, for MUC5B on chromosome 11, was also associated with features of COPD, including chronic bronchitis and acute exacerbations, in one COPD study population but not another. Results from a much larger study, the UK Biobank, indicate that this variant is associated with chronic mucus production and chronic cough, which are key features of chronic bronchitis. Thus, we conclude that the concentration of key proteins in mucus are influenced by genetic variation, and that a variant on chromosome 11 that affects MUC5B may in turn alter COPD outcomes.

genetics↗