Biology subjects

O'Connor, M. J.

Publications and source records attributed to O'Connor, M. J..

6 recordsLinked to original sources

bioRxiv2026

The HuBMAP Framework for Advancing Data FAIRness

Since publication of the FAIR Guiding Principles in 2016, the scientific community has increasingly sought to make experimental data findable, accessible, interoperable, and reusable. Operationalizing the FAIR principles in routine scientific workflows remains challenging without a standardized, workable infrastructure. With over 10,000 datasets from over 40 institutions, spanning more than 50 diverse assay types ranging from single-cell sequencing technologies to 2D and 3D spatial omics, the U.S. National Institutes of Health (NIH) Human Bio-Molecular Atlas Program (HuBMAP) consortium has been ideally situated to create a FAIR ecosystem. With the goal of achieving data "FAIRness," HuBMAP developed and implemented well-defined, community-endorsed metadata reporting standards across the research lifecycle. These reporting standards include detailed schemas, harmonized across a multitude of assays, that define the metadata associated with a dataset and the organization of the corresponding data files. These standards ensure documentation of the data collection process, of the data themselves, and of the manner in which the data are packaged for sharing, while remaining compliant with the Health Insurance Portability and Accountability Act (HIPAA). The use of these reporting standards, in tandem with technology to foster adherence, allows HuBMAP to fulfill its goal of generating FAIR data for open dissemination through its Data Portal and Human Reference Atlas. The procedures and simple workflow adopted by HuBMAP investigators serve as a model for other scientific communities aiming to maximize the value of varied datasets addressing a shared research question. The HuBMAP end-to-end, metadata-centered workflow has been replicated and enhanced by the NIH Cellular Senescence Network (SenNet) consortium and is readily available through open-source technology for others to utilize.

cell biology↗

bioRxiv2025

Multi-omics decipher the molecular mechanisms driving high-lipid production in an artificially-evolved Chlamydomonas mutant

Enhancing lipid accumulation in microalgae is critical for commercial viability but often compromises growth. We previously identified an artificially evolved Chlamydomonas reinhardtii mutant (H5) that retains wild-type growth (CC-503) while producing significantly more lipids. Here, we present multi-omic analyses that elucidate the molecular basis of this phenotype. Whole-genome sequencing revealed over 3,000 mutations in H5, including 45 in protein-coding genes (e.g., phosphofructokinase, acyl-carrier protein, glycerol kinase). Six corresponding CLiP insertion mutants also showed elevated lipid content. Transcriptomics revealed upregulation of key genes for glycolysis, nutrient uptake, and proliferation (e.g., pyruvate carboxylase, carbonic anhydrase) under nutrient-replete conditions. Metabolomics identified a striking increase in malonate, a metabolite that supports fatty acid synthesis and cell proliferation. Epigenomic profiling showed hypomethylation in triacylglycerol (TAG) biosynthesis genes and hypermethylation in energy balance regulators. Together, these data suggest that accelerated glycolysis and streamlined metabolism drive lipid accumulation in H5 without compromising growth. Our findings provide a blueprint for engineering high-lipid microalgal strains for industrial applications. HIGHLIGHTSO_LIHigh-lipid Chlamydomonas mutant (H5) exhibits cancer-like metabolism: pseudo-hypoxia and nutrient deprivation response C_LIO_LIMulti-omics reveals 45 high-impact mutations synergistically enhance lipid production in H5 C_LIO_LISix CLiP mutants of H5-disrupted genes showed significantly increased lipid content C_LIO_LIMalonate levels increased 10-fold in H5, indicating altered mitochondrial function C_LIO_LIH5 upregulates glycolytic genes while maintaining wild-type growth rates C_LIO_LITranscriptomes from H5 and CC-503 converge after nitrogen deprivation despite replete-state differences C_LIO_LIH5 shows altered lipid composition with increased TAG diversity, decreased DAGs C_LIO_LIEpigenomic profiling reveals 14,720 differentially methylated transcribed regions in H5 C_LI

genomics↗

bioRxiv2025

Gap scheduling of a PARP inhibitor and nanoparticle TOP1 agent combination avoids synergistic bone marrow toxicity

Although combinations of DNA damage response inhibitors (DDRi) and DNA damaging chemotherapy enhance cytotoxicity in cell-based systems, clinical success has been limited by overlapping bone marrow toxicities. Here, we show that a tumor-targeted nanoparticle camptothecin CRLX101, administered concurrently with DDRi, enhances anti-tumour efficacy but also increases bone marrow toxicity in preclinical models. Using rat bone marrow progenitor cells as biomarkers and leveraging differential repair kinetics of CRLX101-induced DNA damage in tumour and bone marrow, we identified a gap schedule of the PARP inhibitor olaparib and CRLX101 that enhanced efficacy over single agents but demonstrated a reduced combination marrow toxicity. A clinical trial has been designed using the gap schedule identified here and represents a template that can be used to successfully deliver DDRi with tumor-targeted chemotherapy in combination.

cancer biology↗

bioRxiv2025

Androgen receptor inhibition extends PARP inhibitor activity in prostate cancer models beyond BRCA mutations and defects in homologous recombination repair.

Recent phase 3 clinical trial readouts have shown benefit of the combination of poly(ADP-ribose) polymerase inhibitors (PARPi) with androgen receptor (AR) pathway inhibitors (ARPi) in metastatic, castration-resistant prostate cancer (mCRPC). While benefit was particularly evident in patients with tumours harbouring mutations in homologous recombination repair (HRR) genes, improved outcomes were also observed in patients with no such defined alterations in their cancers. Although there is literature linking AR activity with DNA repair pathways, the basis of the interaction between the AR and PARP is unclear. Here, we show that benefit of the combination of ARPi and PARPi in prostate cancer in vitro and in vivo models with no HRR mutations requires ARPi-responsive cells and a PARPi with PARP1-trapping activity, and does not involve an effect of PARPi treatment in modulating the transcriptional role of the AR. Combination benefit is driven by an increase in DNA damage in the form of DNA double-strand breaks and micronuclei formation, which is not due to a direct control of HRR gene transcription by the AR. In addition, we uncover a novel role of PARP1 in modulating AR recruitment to chromatin in the presence of DNA damage. These data shed new light on the interplay between PARP1 and the AR in dealing with genotoxic insults and provide a mechanism of action consistent with the observed clinical benefit of the combination of PARPi and ARPi in patients with prostate cancer. Statement of significanceCombination of androgen receptor pathway inhibitors and PARP inhibitors has shown efficacy in prostate cancer. We provide a mechanistic explanation through increased DNA damage accumulation observed in combination vs single-agent treatments.

cancer biology↗

bioRxiv2022

Drug-gene interaction screens coupled to tumour data analyses identify the most clinically-relevant cancer vulnerabilities driving sensitivity to PARP inhibition

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently indicated for the treatment of ovarian, breast, pancreatic and prostate cancers harbouring mutations in the tumour suppressor genes BRCA1 or BRCA2. In the case of ovarian and prostate cancers, their classification as homologous recombination repair (HRR) deficient (HRD) or mutated (HRRm) also makes PARPi an available treatment option beyond BRCA1 or BRCA2 mutational status. However, identification of the most relevant genetic alterations driving the HRD phenotype has proven difficult and recent data have shown that other genetic alterations not affecting HRR are also capable of driving PARPi responses. To gain insight into the genetics driving PARPi sensitivity, we performed CRISPR-Cas9 loss-of-function screens in 6 PARPi-insensitive cell lines and combined the output with published PARPi datasets from 8 additional cell lines. Ensuing exploration of the data identified 110 genes whose inactivation is strongly linked to sensitivity to PARPi. Parallel cell line generation of isogenic gene knockouts in ovarian and prostate cancer cell lines identified that inactivation of core HRR factors is required for driving in vitro PARPi responses comparable to the ones observed for BRCA1 or BRCA2 mutations. Moreover, pan-cancer genetic, transcriptomic and epigenetic data analyses of these 110 genes highlight the ones most frequently inactivated in tumours, making this study a valuable resource for prospective identification of potential PARPi-responsive patient populations. Importantly, our investigations uncover XRCC3 gene silencing as a potential new prognostic biomarker of PARPi sensitivity in prostate cancer. Statement of significanceThis study identifies tumour genetic backgrounds where to expand the use of PARP inhibitors beyond mutations in BRCA1 or BRCA2. This is achieved by combining the output of unbiased genome-wide loss-of-function CRISPR-Cas9 genetic screens with bioinformatics analysis of biallelic losses of the identified genes in public tumour datasets, unveiling loss of the DNA repair gene XRCC3 as a potential biomarker of PARP inhibitor sensitivity in prostate cancer.

cancer biology↗

bioRxiv2020

A meta-analysis of clinical cases of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance

Germline mutations in the BRCA1 or BRCA2 genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies. Tumours from these patients tend to lose both copies of the wild type BRCA gene, which makes them exquisitely sensitive to platinum drugs and PARP inhibitors (PARPi), treatments of choice in these disease settings. Reversion secondary mutations with the capacity of restoring BRCA protein expression have been documented in the literature as bona fide mechanisms of resistance to these treatments. Here, we perform a detailed analysis of clinical cases of reversion mutations described in BRCA1 and BRCA2, which underlines the different importance of BRCA protein domains in contributing to resistance and the potential key role of mutagenic end-joining DNA repair pathways in generating reversions. Our analyses suggest that pharmacological inhibition of these repair pathways could improve durability of drug treatments and highlights potential interventions to both prevent the appearance of reversions and provide new therapeutic opportunities after their acquisition. HighlightsO_LIComprehensive analysis of reversion mutations in BRCA genes identified in clinical cases of resistance to platinum or PARPi C_LIO_LIRevertant proteins devoid of parts of the original sequence, identifying key protein functions involved in resistance C_LIO_LIHypomorph revertant BRCA proteins suggest potential new therapeutic opportunities to overcome resistance C_LIO_LIPrevalence of mutational end-joining DNA repair mechanisms leading to reversions, especially in those affecting BRCA2 C_LIO_LIPharmacological inhibition of mutational end-joining DNA repair could improve durability of drug treatments C_LI

cancer biology↗