Biology subjects

Pritchard, C.

Publications and source records attributed to Pritchard, C..

8 recordsLinked to original sources

bioRxiv2026

A pan-cohort transcriptional landscape of breast cancer maps subtype and microenvironmental programs

Breast cancer comprises heterogeneous transcriptional states that are incompletely captured by discrete clinical or molecular subtype labels. To visualize this heterogeneity in a unified framework, we integrated bulk RNA-seq data from 2,284 patient samples across 13 studies using 18,089 protein coding genes, a harmonized processing pipeline, batch correction, consensus clustering and PaCMAP dimensionality reduction to construct an interactive breast cancer transcriptional landscape. Consensus clustering identified five major regions, which were annotated using PAM50 scores calculated for each sample: Luminal A, Luminal B, HER2 enriched, and two basal associated clusters. The basal clusters separated into an immune rich region marked by T cell-inflamed, tumor-associated macrophages (TAM), and low-purity signatures, and a cell-cycle driven region enriched for proliferation and DNA replication programs. Overlay of marker genes, pathways, kinases, neuronal like signaling programs, cancer associated fibroblasts (CAF) states, and TAM programs revealed spatially organized subtype biology and microenvironmental heterogeneity. Finally, projection of therapy associated resistance signatures identified landscape regions linked to predicted resistance to HER2-targeted therapy and hormone receptor directed endocrine therapies. By enabling interactive exploration of transcriptional states, marker genes, pathways, and therapeutic response programs, this resource provides a community framework for biomarker discovery in breast cancer.

bioinformatics↗

bioRxiv2026

Beyond Histology: A Unified Transcriptomic Atlas Defines Lung Cancer Biologic States and Subtypes

Lung cancer encompasses multiple histological entities with substantial molecular heterogeneity that remain incompletely resolved at population scale. Here, we constructed a unified reference landscape of lung cancer by analyzing raw RNA sequencing data from 1,824 tumors spanning adenocarcinoma (n=966), squamous cell carcinoma (n=628), small cell lung cancer (n=150), and unclassified non small cell lung cancer (n=80). Following batch correction, samples were analyzed using consensus clustering and visualized with PaCMAP to generate a molecular atlas annotated with clinical and biological metadata. Rather than segregating by pathological diagnosis, tumors organized along conserved transcriptional axes defined by tumor-intrinsic biology including proliferative or metabolic programs and immune-infiltrated states. Consensus clustering resolved nine robust molecular clusters, including an adenocarcinoma-associated subgroup, a neuroendocrine-like adenocarcinoma marked by ASCL1 activation, immune-associated regions, and bifurcation of both small cell and squamous carcinomas into biologically distinct states. Spatially restricted expression of selected clinically relevant transcripts nominated state-specific therapeutic hypotheses requiring future functional and clinical validation. Projection of patient tumors and patient-derived xenografts onto the atlas demonstrated preservation of transcriptional identity and enabled quantitative assessment of model fidelity. This integrated framework organizes lung cancer as a structured continuum of transcriptional states and provides a reference resource for biological interpretation and future translational studies.

bioinformatics↗

bioRxiv2025

Moving Beyond Binary Biomarkers: Machine Learning Model Resolves Concurrent and Molecularly Heterogeneous Mismatch Repair and Homologous Recombination Deficiencies in Prostate Cancer

Current DNA damage repair (DDR) biomarkers employ binary classifications that fail to capture the molecular complexity of tumors with concurrent repair deficiencies. We used genomics analysis to stratify 672 metastatic prostate cancer patients into 11 DDR subgroups, identifying 51 molecular signatures with weighted roles in class identity. We identified a tumor-mutational-burden very-high subset, characterized by 19 mutations/Mb or more, as a molecularly distinct group characterized by preserved genomic integrity and enhanced immunogenicity. Critically, 2.3 percent of tumors exhibited concurrent TMB-High and HRR mutant phenotypes, while 1.5 percent harbored MMR bi-allelic loss without MMRd (mismatch-repair-deficiency) signatures. Clinical validation in 130 patients demonstrated superior immunotherapy responses in tumors with very high TMB levels. We developed CHIMERA DDR, a probabilistic machine learning tool that integrates these 51 genomic features using a nested Random Forest architecture to infer seven clinically relevant DDR subgroups. After negating model overfit concerns, CHIMERA-DDR showed exceptional classification performance (AUCs 0.919-0.999) to accurately detect MMRd and HRR mutant molecular subtypes with or without concurrent DDR deficiencies, resolving admixed phenotypes to enable precision therapeutic stratification beyond binary methods.

genomics↗

bioRxiv2024

Estimating the seroprevalence of tuberculosis (Mycobacterium bovis) infection in a wild deer population in southwest England

Bovine tuberculosis (bTB) is a major disease of cattle that is subject to an eradication strategy in England. To inform control policies and manage the epidemic, all potential sources of infection for cattle must be identified and understood. The causative agent of bTB, Mycobacterium bovis, has a wide host range including several deer species. While transmission between cattle and deer has been implicated in some localised endemic regions, the role of deer in the epidemiology of bTB in England is poorly understood. This paper presents the results of a serological survey to estimate the prevalence of M. bovis in a large wild deer population in the High bTB Risk Area of southwest England. Blood samples were collected post-mortem over a 12-month period from wild deer during annual deer management controls in the Exmoor area and tested for M. bovis serum antibodies. Overall, 432 samples were collected and 69 (16.0%) were seropositive. The true seroprevalence in our sample was estimated to be 29.2% (95% CrI 21.1-38.6%), using Bayesian Latent Class Analysis to account for imperfect diagnostic test accuracy. Prevalence did not appear to differ between sexes nor between species, although the sample was predominantly red deer. The lowest prevalence was observed in animals aged under 1-year. Whilst these results provide valuable insights into M. bovis seroprevalence in this wild deer population, they should be interpreted alongside other relevant information such as ecology, species-specific epidemiology and disease pathology, deer density and cattle management to inform potential transmission risks between cattle and wild deer.

zoology↗

bioRxiv2024

Molecular consequences of acute versus chronic CDK12 loss in prostate carcinoma nominates distinct therapeutic strategies

Genomic loss of the transcriptional kinase CDK12 occurs in [~]6% of metastatic castration-resistant prostate cancers (mCRPC) and correlates with poor patient outcomes. Prior studies demonstrate that acute CDK12 loss confers a homologous recombination (HR) deficiency (HRd) phenotype via premature intronic polyadenylation (IPA) of key HR pathway genes, including ATM. However, mCRPC patients have not demonstrated benefit from therapies that exploit HRd such as inhibitors of polyADP ribose polymerase (PARP). Based on this discordance, we sought to test the hypothesis that an HRd phenotype is primarily a consequence of acute CDK12 loss and the effect is greatly diminished in prostate cancers adapted to CDK12 loss. Analyses of whole genome sequences (WGS) and RNA sequences (RNAseq) of human mCRPCs determined that tumors with biallelic CDK12 alterations (CDK12BAL) lack genomic scar signatures indicative of HRd, despite carrying bi-allelic loss and the appearance of the hallmark tandem-duplicator phenotype (TDP). Experiments confirmed that acute CDK12 inhibition resulted in aberrant polyadenylation and downregulation of long genes (including BRCA1 and BRCA2) but such effects were modest or absent in tumors adapted to chronic CDK12BAL. One key exception was ATM, which did retain transcript shortening and reduced protein expression in the adapted CDK12BAL models. However, CDK12BALcells demonstrated intact HR as measured by RAD51 foci formation following irradiation. CDK12BAL cells showed a vulnerability to targeting of CDK13 by sgRNA or CDK12/13 inhibitors and in vivo treatment of prostate cancer xenograft lines showed that tumors with CDK12BALresponded to the CDK12/13 inhibitor SR4835, while CDK12-intact lines did not. Collectively, these studies show that aberrant polyadenylation and long HR gene downregulation is primarily a consequence of acute CDK12 deficiency, which is largely compensated for in cells that have adapted to CDK12 loss. These results provide an explanation for why PARPi monotherapy has thus far failed to consistently benefit patients with CDK12 alterations, though alternate therapies that target CDK13 or transcription are candidates for future research and testing.

cancer biology↗

bioRxiv2021

LY-CoV1404 potently neutralizes SARS-CoV-2 variants

SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization when administered early during COVID-19 disease. However, the emergence of variants of concern has negatively impacted the therapeutic use of some authorized mAbs. Using a high throughput B-cell screening pipeline, we isolated a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody called LY-CoV1404 (also known as bebtelovimab). LY-CoV1404 potently neutralizes authentic SARS-CoV-2 virus, including the prototype, B.1.1.7, B.1.351 and B.1.617.2). In pseudovirus neutralization studies, LY-CoV1404 retains potent neutralizing activity against numerous variants including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant and retains binding to spike proteins with a variety of underlying RBD mutations including K417N, L452R, E484K, and N501Y. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved with the exception of N439 and N501. Notably, the binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The breadth of reactivity to amino acid substitutions present among current VOC together with broad and potent neutralizing activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants causing COVID-19. In BriefLY-CoV1404 is a potent SARS-CoV-2-binding antibody that neutralizes all known variants of concern and whose epitope is rarely mutated. HighlightsO_LILY-CoV1404 potently neutralizes SARS-CoV-2 authentic virus and known variants of concern including the B.1.1.529 (Omicron), the BA.2 Omicron subvariant, and B.1.617.2 (Delta) variants C_LIO_LINo loss of potency against currently circulating variants C_LIO_LIBinding epitope on RBD of SARS-CoV-2 is rarely mutated in GISAID database C_LIO_LIBreadth of neutralizing activity and potency supports clinical development C_LI

immunology↗

bioRxiv2020

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

Altering ubiquitination by disruption of individual deubiquitinating enzymes (DUBs) has proven to affect hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. To accomplish this goal, we systematically inactivated DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNAs (shRNAs) screens. We found that multiple DUBs may be individually required for hematopoiesis and that the ubiquitin-specific protease 15 (USP15) is particularly important for the maintenance of murine hematopoietic stem and progenitor cells in vitro and in vivo. Consistently, Usp15 knockout mice exhibited a reduced HSC pool. The defect was intrinsic to HSCs, as demonstrated by competitive repopulation assays. Importantly, USP15 is highly expressed in normal human hematopoietic cells and leukemias, and USP15 depletion in murine early progenitors and myeloid leukemia cells impaired in vitro expansion and increased genotoxic stress. Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSC and in leukemia cells.

genetics↗

bioRxiv2016

Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression

About 16% of breast cancers fall into a clinically aggressive category designated triple negative (TNBC) due to a lack of ERBB2, estrogen receptor and progesterone receptor expression1-3. The mutational spectrum of TNBC has been characterized as part of The Cancer Genome Atlas (TCGA)4; however, snapshots of primary tumors cannot reveal the mechanisms by which TNBCs progress and spread. To address this limitation we initiated the Intensive Trial of OMics in Cancer (ITOMIC)-001, in which patients with metastatic TNBC undergo multiple biopsies over space and time5. Whole exome sequencing (WES) of 67 samples from 11 patients identified 426 genes containing multiple distinct single nucleotide variants (SNVs) within the same sample, instances we term Multiple SNVs affecting the Same Gene and Sample (MSSGS). We find that >90% of MSSGS result from cis-compound mutations (in which both SNVs affect the same allele), that MSSGS comprised of SNVs affecting adjacent nucleotides arise from single mutational events, and that most other MSSGS result from the sequential acquisition of SNVs. Some MSSGS drive cancer progression, as exemplified by a TNBC driven by FGFR2(S252W;Y375C). MSSGS are more prevalent in TNBC than other breast cancer subtypes and occur at higher-than-expected frequencies across TNBC samples within TCGA. MSSGS may denote genes that play as yet unrecognized roles in cancer progression.

clinical trials↗