Weaverly Colleen Lee

All Publications

• Mechanisms of ferroptosis sensitization and resistance. Developmental cell Lee, W. C., Dixon, S. J. 2025; 60 (7): 982-993

  Abstract

  Ferroptosis is an iron-dependent and oxidative form of non-apoptotic cell death with roles in development, homeostasis, and disease. Ferroptosis sensitivity can vary between cells, often for reasons that are not well understood. In this perspective, we describe the core ferroptosis mechanism and outline how changes in iron, redox, and lipid metabolism can alter ferroptosis sensitivity. We propose the concept of a ferroptosis sensitivity-resistance continuum to describe how different intrinsic and extrinsic factors interact to push cells toward a more ferroptosis-sensitive or ferroptosis-resistant state, with effects on development and diseases such as cancer.

  View details for DOI 10.1016/j.devcel.2025.02.004

  View details for PubMedID 40199240

• A clinical drug candidate that triggers non-apoptotic cancer cell death. Research square Dixon, S., Leak, L., Wang, Z., Lee, W. C., Johnson, B., Millner, A., Ko, P. J., Decosto, C., Magtanong, L., Ritho, J., Skouta, R., Atilla-Gokcumen, E., Myers, C., Moffat, J., Boone, C., Bensinger, S., Moding, E., Joseph, A., Chan, A., Chitkara, S., Salinas, J., Nathanson, D. 2025

  Abstract

  Small molecules that induce non-apoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here, we report that tegavivint, a drug candidate undergoing human clinical trials, can activate a unique mechanism of non-apoptotic cell death in sarcomas and other cancer cells. This lethal mechanism is distinct from ferroptosis, necroptosis and pyroptosis and requires the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase (TECR). TECR is canonically involved in the synthesis of very long chain fatty acids but appears to promote non-apoptotic cell death in response to CIL56 and tegavivint via the synthesis of the saturated long-chain fatty acid palmitate. These findings outline a lipid-dependent non-apoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans.

  View details for DOI 10.21203/rs.3.rs-4138879/v1

  View details for PubMedID 39989975

  View details for PubMedCentralID PMC11844650

• BMP SIGNALING MODULATES APOPTOTIC AND NON-APOPTOTIC CELL DEATH IN GLIOBLASTOMA Lee, W., Salinas, J., Nathanson, D., Dixon, S. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0512

  View details for Web of Science ID 001362477700023

• Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders. Disease models & mechanisms Crombie, E. M., Korecki, A. J., Cleverley, K., Adair, B. A., Cunningham, T. J., Lee, W. C., Lengyell, T. C., Maduro, C., Mo, V., Slade, L. M., Zouhair, I., Fisher, E. M., Simpson, E. M. 2024

  Abstract

  The TATA-box binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked Dystonia-Parkinsonism, a neurodegenerative disorder. However, this field has suffered from the lack of a genetic mouse model of TAF1 disease to explore mammalian mechanism and treatments. Here, we generated and validated a conditional cre-lox allele, and the first ubiquitous Taf1 knock-out mouse. We discovered that Taf1 deletion in males was embryonically lethal, which may explain why no human null-variants have been identified. In the brains of Taf1 heterozygous females, no differences were found in gross structure, overall expression, and protein localization, suggesting extreme skewed X-inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting a small subset of neurons has been negatively impacted by Taf1 loss. Finally, this new mouse may be a future platform for the development of TAF1 disease therapeutics.

  View details for DOI 10.1242/dmm.050741

  View details for PubMedID 38804708

• Protocol for detection of ferroptosis in cultured cells. STAR protocols Murray, M. B., Leak, L. B., Lee, W. C., Dixon, S. J. 2023; 4 (3): 102457

  Abstract

  Mammalian cells can die by apoptosis or by one of several non-apoptotic mechanisms, such as ferroptosis. Here, we present a protocol to distinguish ferroptosis from other cell death mechanisms in cultured cells. We describe steps for seeding cells, administering mechanism-specific cell death inducers and inhibitors, and measuring cell death and viability. We then detail the use of molecular markers to verify mechanisms of cell death. This protocol can be used to identify and distinguish ferroptosis in 2D and 3D cultures. For complete details on the use and execution of this protocol, please refer to Ko, et al. (2019),1 Magtanong, et al. (2022),2 and Armenta, et al. (2022).3.

  View details for DOI 10.1016/j.xpro.2023.102457

  View details for PubMedID 37556320

• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A NATURE Brown, A., Wilkins, O. G., Keuss, M. J., Hill, S. E., Zanovello, M., Lee, W., Bampton, A., Lee, F. Y., Masino, L., Qi, Y. A., Bryce-Smith, S., Gatt, A., Hallegger, M., Fagegaltier, D., Phatnani, H., Newcombe, J., Gustavsson, E. K., Seddighi, S., Reyes, J. F., Coon, S. L., Ramos, D., Schiavo, G., Fisher, E. C., Raj, T., Secrier, M., Lashley, T., Ule, J., Buratti, E., Humphrey, J., Ward, M. E., Fratta, P., NYGC ALS Consortium 2022; 603 (7899): 131-+

  Abstract

  Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1-3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

  View details for DOI 10.1038/s41586-022-04436-3

  View details for Web of Science ID 000760257200005

  View details for PubMedID 35197628

  View details for PubMedCentralID PMC8891020

• NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease SCIENTIFIC REPORTS Maza, A., Jarvis, S., Lee, W., Cunningham, T. J., Schiavo, G., Secrier, M., Fratta, P., Sleigh, J. N., Fisher, E. C., Sudre, C. H. 2021; 11 (1): 12251

  Abstract

  The neuromuscular junction (NMJ) is the peripheral synapse formed between a motor neuron axon terminal and a muscle fibre. NMJs are thought to be the primary site of peripheral pathology in many neuromuscular diseases, but innervation/denervation status is often assessed qualitatively with poor systematic criteria across studies, and separately from 3D morphological structure. Here, we describe the development of 'NMJ-Analyser', to comprehensively screen the morphology of NMJs and their corresponding innervation status automatically. NMJ-Analyser generates 29 biologically relevant features to quantitatively define healthy and aberrant neuromuscular synapses and applies machine learning to diagnose NMJ degeneration. We validated this framework in longitudinal analyses of wildtype mice, as well as in four different neuromuscular disease models: three for amyotrophic lateral sclerosis (ALS) and one for peripheral neuropathy. We showed that structural changes at the NMJ initially occur in the nerve terminal of mutant TDP43 and FUS ALS models. Using a machine learning algorithm, healthy and aberrant neuromuscular synapses are identified with 95% accuracy, with 88% sensitivity and 97% specificity. Our results validate NMJ-Analyser as a robust platform for systematic and structural screening of NMJs, and pave the way for transferrable, and cross-comparison and high-throughput studies in neuromuscular diseases.

  View details for DOI 10.1038/s41598-021-91094-6

  View details for Web of Science ID 000663785600001

  View details for PubMedID 34112844

  View details for PubMedCentralID PMC8192785

• A novel knockout mouse for the small EDRK-rich factor 2 (Serf2) showing developmental and other deficits MAMMALIAN GENOME Cleverley, K., Lee, W., Mumford, P., Collins, T., Rickman, M., Cunningham, T. J., Cleak, J., Mianne, J., Szoke-Kovacs, Z., Stewart, M., Teboul, L., Maduro, C., Wells, S., Wiseman, F. K., Fisher, E. C. 2021; 32 (2): 94-103

  Abstract

  The small EDRK-rich factor 2 (SERF2) is a highly conserved protein that modifies amyloid fibre assembly in vitro and promotes protein misfolding. However, the role of SERF2 in regulating age-related proteotoxicity remains largely unexplored due to a lack of in vivo models. Here, we report the generation of Serf2 knockout mice using an ES cell targeting approach, with Serf2 knockout alleles being bred onto different defined genetic backgrounds. We highlight phenotyping data from heterozygous Serf2+/- mice, including unexpected male-specific phenotypes in startle response and pre-pulse inhibition. We report embryonic lethality in Serf2-/- null animals when bred onto a C57BL/6 N background. However, homozygous null animals were viable on a mixed genetic background and, remarkably, developed without obvious abnormalities. The Serf2 knockout mice provide a powerful tool to further investigate the role of SERF2 protein in previously unexplored pathophysiological pathways in the context of a whole organism.

  View details for DOI 10.1007/s00335-021-09864-6

  View details for Web of Science ID 000628461600001

  View details for PubMedID 33713180

  View details for PubMedCentralID PMC8012326