James M. McFarland
A5069336326- Cancer Genomics and Diagnostics
- FOXO transcription factor regulation
- Bioinformatics and Genomic Networks
- Genetics, Bioinformatics, and Biomedical Research
- Ferroptosis and cancer prognosis
- Renal and related cancers
- Single-cell and spatial transcriptomics
- CRISPR and Genetic Engineering
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Evolution and Genetic Dynamics
- Neural dynamics and brain function
- Cancer Mechanisms and Therapy
- Cell Image Analysis Techniques
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Protein Degradation and Inhibitors
- Cancer Cells and Metastasis
- Neuroscience and Neuropharmacology Research
- Advanced biosensing and bioanalysis techniques
- Pancreatic and Hepatic Oncology Research
- Gene Regulatory Network Analysis
- Molecular Biology Techniques and Applications
- Memory and Neural Mechanisms
- Computational Drug Discovery Methods
Broad Institute
2017-2024
Brown University
2011-2024
Massachusetts Institute of Technology
2019-2023
German Cancer Research Center
2023
Hopp Children's Cancer Center Heidelberg
2023
Heidelberg University
2023
Sabin Vaccine Institute
2023
University of Cincinnati
2023
Dana-Farber Cancer Institute
2018-2023
University of Montana
2020-2021
The availability of multiple datasets comprising genome-scale RNAi viability screens in hundreds diverse cancer cell lines presents new opportunities for understanding vulnerabilities. Integrated analyses these data to assess differential dependency across genes and are challenging due confounding factors such as batch effects variable screen quality, well difficulty assessing gene on an absolute scale. To address issues, we incorporated line screen-quality parameters hierarchical Bayesian...
Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited.To examine these attributes systematically, we profiled metastatic biopsies matched organoid models at single-cell resolution.In vivo, identify a new intermediate PDAC transcriptional cell state uncover distinct site-and state-specific tumor microenvironments (TMEs).Benchmarking against this...
CRISPR loss of function screens are powerful tools to interrogate biology but exhibit a number biases and artifacts that can confound the results. Here, we introduce Chronos, an algorithm for inferring gene knockout fitness effects based on explicit model cell proliferation dynamics after knockout. We test Chronos two pan-cancer datasets one longitudinal screen. generally outperforms competitors in separation controls strength biomarker associations, particularly when data is available....
Abstract CRISPR-Cas9 viability screens are increasingly performed at a genome-wide scale across large panels of cell lines to identify new therapeutic targets for precision cancer therapy. Integrating the datasets resulting from these studies is necessary adequately represent heterogeneity human cancers and assemble comprehensive map genetic vulnerabilities. Here, we integrated two largest public independent date (at Broad Sanger institutes) by assessing, comparing, selecting methods...
Cell lines are key tools for preclinical cancer research, but it remains unclear how well they represent patient tumor samples. Direct comparisons of and cell line transcriptional profiles complicated by several factors, including the variable presence normal cells in We thus develop an unsupervised alignment method (Celligner) apply to integrate large-scale RNA-Seq datasets. Although our aligns majority with samples same type, also reveals large differences similarity across lines. Using...
The computation represented by a sensory neuron's response to stimuli is constructed from an array of physiological processes both belonging that neuron and inherited its inputs. Although many these are known be nonlinear, linear approximations commonly used describe the stimulus selectivity neurons (i.e., receptive fields). Here we present approach for modeling processing, termed Nonlinear Input Model (NIM), which based on hypothesis dominant nonlinearities imposed mechanisms arise...
Abstract Assays to study cancer cell responses pharmacologic or genetic perturbations are typically restricted using simple phenotypic readouts such as proliferation rate. Information-rich assays, gene-expression profiling, have generally not permitted efficient profiling of a given perturbation across multiple cellular contexts. Here, we develop MIX-Seq, method for multiplexed transcriptional post-perturbation mixture samples with single-cell resolution, SNP-based computational...
Abstract Saccadic eye movements play a central role in primate vision. Yet, relatively little is known about their effects on the neural processing of visual inputs. Here we examine this question primary cortex (V1) using receptive-field-based models, combined with an experimental design that leaves retinal stimulus unaffected by saccades. This approach allows us to analyse V1 during saccades unprecedented detail, revealing robust perisaccadic modulation. In particular, produce biphasic...
Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress cell cycle delays, foremost G1 S phase. Here, we investigate how aneuploidy both slow proliferation disease outcome. We test hypothesis that brings about resistance to chemotherapies because of a general feature aneuploid condition-G1 delays. show single lead increased frontline chemotherapeutics cisplatin paclitaxel....
Abstract Systematic identification of signaling pathways required for the fitness cancer cells will facilitate development new therapies. We used gene essentiality measurements in 1,086 cell lines to identify selective coessentiality modules and found that a ubiquitin ligase complex composed UBA6, BIRC6, KCMF1, UBR4 is survival subset epithelial tumors exhibit high degree aneuploidy. Suppressing BIRC6 are dependent on this led substantial reduction vitro potent tumor regression vivo....
The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to current standard of care. Therefore, an attractive anticancer target. Here we describe BRD-810 as a potent selective inhibitor its key design principle rapid systemic clearance potentially minimize area under curve-driven toxicities associated with inhibition. induced killing within 4 h vitro but, same 4-h window, had no impact on viability or...