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Sullivan, James

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Sullivan

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Sullivan, James

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2014 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.e7cc9623-bd69-4bc5-bde9-e41ac2c88916

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    Brain Tumor Cells in Circulation Are Enriched for Mesenchymal Gene Expression
    (American Association for Cancer Research (AACR), 2014) Sullivan, James; Nahed, Brian; Madden, M. W.; Oliveira, S. M.; Springer, S.; Bhere, Deepak; Chi, A. S.; Wakimoto, Hiroaki; Rothenberg, S. M.; Sequist, Lecia; Kapur, R.; Shah, Khalid; Iafrate, Anthony; Curry, William; Loeffler, Jay; Batchelor, Tracy; Louis, David; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel
    Glioblastoma (GBM) is a highly aggressive brain cancer characterized by local invasion and angiogenic recruitment, yet metastatic dissemination is extremely rare. Here, we adapted a microfluidic device to deplete hematopoietic cells from blood specimens of patients with GBM, uncovering evidence of circulating brain tumor cells (CTCs). Staining and scoring criteria for GBM CTCs were first established using orthotopic patient-derived xenografts (PDX), and then applied clinically: CTCs were identified in at least one blood specimen from 13/33 patients (39%; 26/87 samples). Single GBM CTCs isolated from both patients and mouse PDX models demonstrated enrichment for mesenchymal over neural differentiation markers, compared with primary GBMs. Within primary GBMs, RNA-in-situ hybridization identifies a subpopulation of highly migratory mesenchymal tumor cells, and in a rare patient with disseminated GBM, systemic lesions were exclusively mesenchymal. Thus, a mesenchymal subset of GBM cells invades into the vasculature, and may proliferate outside the brain.
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    Expression of β-globin by cancer cells promotes cell survival during blood-borne dissemination
    (Nature Publishing Group, 2017) Zheng, Yu; Miyamoto, David; Wittner, Ben; Sullivan, James; Aceto, Nicola; Jordan, Nicole Vincent; Yu, Min; Karabacak, Nezihi; Comaills, Valentine; Morris, Robert; Desai, Rushil; Desai, Niyati; Emmons, Erin; Milner, John D.; Lee, Richard; Wu, Chin-Lee; Sequist, Lecia; Haas, Wilhelm; Ting, David; Toner, Mehmet; Ramaswamy, Sridhar; Maheswaran, Shyamala; Haber, Daniel
    Metastasis-competent circulating tumour cells (CTCs) experience oxidative stress in the bloodstream, but their survival mechanisms are not well defined. Here, comparing single-cell RNA-Seq profiles of CTCs from breast, prostate and lung cancers, we observe consistent induction of β-globin (HBB), but not its partner α-globin (HBA). The tumour-specific origin of HBB is confirmed by sequence polymorphisms within human xenograft-derived CTCs in mouse models. Increased intracellular reactive oxygen species (ROS) in cultured breast CTCs triggers HBB induction, mediated through the transcriptional regulator KLF4. Depletion of HBB in CTC-derived cultures has minimal effects on primary tumour growth, but it greatly increases apoptosis following ROS exposure, and dramatically reduces CTC-derived lung metastases. These effects are reversed by the anti-oxidant N-Acetyl Cysteine. Conversely, overexpression of HBB is sufficient to suppress intracellular ROS within CTCs. Altogether, these observations suggest that β-globin is selectively deregulated in cancer cells, mediating a cytoprotective effect during blood-borne metastasis.