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Hayes, Madeline

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Hayes

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Madeline

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Hayes, Madeline

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2016 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.b998276e-5b73-4d3e-a3e7-d5130bbe3c3f

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    The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma
    (2017) Ignatius, Myron S.; Hayes, Madeline; Lobbardi, Riadh; Chen, Eleanor Y.; McCarthy, Karin M.; Sreenivas, Prethish; Motala, Zainab; Durbin, Adam; Molodtsov, Aleksey; Reeder, Sophia; Jin, Alexander; Sindiri, Sivasish; Beleyea, Brian C.; Bhere, Deepak; Alexander, Matthew S.; Shah, Khalid; Keller, Charles; Linardic, Corinne M.; Nielsen, Petur G.; Malkin, David; Khan, Javed; Langenau, David
    Summary Tumor-propagating cells (TPCs) share self-renewal properties with normal stem cells and drive continued tumor growth. However, mechanisms regulating TPC self-renewal are largely unknown, especially in embryonal rhabdomyosarcoma (ERMS)—a common pediatric cancer of muscle. Here, we used a zebrafish transgenic model of ERMS to identify a role for intracellular NOTCH1 (ICN1) in increasing TPCs by 23-fold. ICN1 expanded TPCs by enabling the de-differentiation of zebrafish ERMS cells into self-renewing myf5+ TPCs, breaking the rigid differentiation hierarchies reported in normal muscle. ICN1 also had conserved roles in regulating human ERMS self-renewal and growth. Mechanistically, ICN1 up-regulated expression of SNAIL1, a transcriptional repressor, to increase TPC number in human ERMS and to block muscle differentiation through suppressing MEF2C, a myogenic differentiation transcription factor. Our data implicate the NOTCH1/SNAI1/MEF2C signaling axis as a major determinant of TPC self-renewal and differentiation in ERMS, raising hope of therapeutically targeting this pathway in the future.
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    Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish
    (Nature Publishing Group, 2016) Tang, Qin; Moore, John C.; Ignatius, Myron S.; Tenente, Inês M.; Hayes, Madeline; Garcia, Elaine; Torres Yordán, Nora; Bourque, Caitlin; He, Shuning; Blackburn, Jessica S.; Look, A.; Houvras, Yariv; Langenau, David
    Cancers contain a wide diversity of cell types that are defined by differentiation states, genetic mutations and altered epigenetic programmes that impart functional diversity to individual cells. Elevated tumour cell heterogeneity is linked with progression, therapy resistance and relapse. Yet, imaging of tumour cell heterogeneity and the hallmarks of cancer has been a technical and biological challenge. Here we develop optically clear immune-compromised rag2E450fs (casper) zebrafish for optimized cell transplantation and direct visualization of fluorescently labelled cancer cells at single-cell resolution. Tumour engraftment permits dynamic imaging of neovascularization, niche partitioning of tumour-propagating cells in embryonal rhabdomyosarcoma, emergence of clonal dominance in T-cell acute lymphoblastic leukaemia and tumour evolution resulting in elevated growth and metastasis in BRAFV600E-driven melanoma. Cell transplantation approaches using optically clear immune-compromised zebrafish provide unique opportunities to uncover biology underlying cancer and to dynamically visualize cancer processes at single-cell resolution in vivo.
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    Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma
    (eLife Sciences Publications, Ltd, 2017) Tenente, Inês M; Hayes, Madeline; Ignatius, Myron S.; McCarthy, Karin; Yohe, Marielle; Sindiri, Sivasish; Gryder, Berkley; Oliveira, Mariana L; Ramakrishnan, Ashwin; Tang, Qin; Chen, Eleanor Y; Petur Nielsen, G; Khan, Javed; Langenau, David
    Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth. DOI: http://dx.doi.org/10.7554/eLife.19214.001