@article{d16ebac078474a51b3358a345f0e80b0,
title = "Toward Minimal Residual Disease-Directed Therapy in Melanoma",
abstract = "Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance. Drug-tolerant cells that persist through treatment of melanoma exhibit multiple transcriptional states, one of which is a key driver that can be targeted therapeutically.",
keywords = "RXR signaling, cutaneous melanoma, drug tolerance, gene regulatory networks, single cell transcriptomics, targeted therapy",
author = "Florian Rambow and Aljosja Rogiers and Oskar Marin-Bejar and Sara Aibar and Julia Femel and Michael Dewaele and Panagiotis Karras and Daniel Brown and Chang, {Young Hwan} and Maria Debiec-Rychter and Carmen Adriaens and Enrico Radaelli and Pascal Wolter and Oliver Bechter and Reinhard Dummer and Mitchell Levesque and Adriano Piris and Frederick, {Dennie T.} and Genevieve Boland and Flaherty, {Keith T.} and {van den Oord}, Joost and Thierry Voet and Stein Aerts and Lund, {Amanda W.} and Marine, {Jean Christophe}",
note = "Funding Information: We thank G. Bervoets for excellent technical assistance and Prof. G. Ghanem for the MM lines. M. Stas and V. Boecxstaens provided samples for the PDX models. PDX experiments were developed by TRACE with the assistance of E. Leucci, L. Rizzotto, F. Amant, E. Hermans, D. Thomas, E. Gomm{\'e}, and K. Crevits. FACS was performed by P.A. Penttila and C. Nkama. The TruSight26 analysis was performed by S. Vander Borght. We thank the University Research Priority Program in translational cancer research for access to the melanoma material. D. Nittner and L. Omodho provided histology support. F.R. received a fellowship from the Omics/Marie Curie@VIB . This work was supported by KUL GOA (# 14/012 ), VLK (Vlaamse Liga tegen Kanker) , Interreg (SKiN-HUID) , and Fonds voor Wetenschappelijk Onderzoek Vlaanderen (# G.0929.16 N). J.F. was supported by the Swedish Research Council . A.W.L. was supported by the OHSU Knight Cancer Center Support grant NIH P30-CA069533 , the Department of Defense Peer Reviewed Cancer Research Program ( W81XWH-15-1-0348 ), V Foundation for Cancer Research ( V2015-024 ), and the Cancer Research Institute and Melanoma Research Alliance . Funding Information: We thank G. Bervoets for excellent technical assistance and Prof. G. Ghanem for the MM lines. M. Stas and V. Boecxstaens provided samples for the PDX models. PDX experiments were developed by TRACE with the assistance of E. Leucci, L. Rizzotto, F. Amant, E. Hermans, D. Thomas, E. Gomm{\'e}, and K. Crevits. FACS was performed by P.A. Penttila and C. Nkama. The TruSight26 analysis was performed by S. Vander Borght. We thank the University Research Priority Program in translational cancer research for access to the melanoma material. D. Nittner and L. Omodho provided histology support. F.R. received a fellowship from the Omics/Marie Curie@VIB. This work was supported by KUL GOA (#14/012), VLK (Vlaamse Liga tegen Kanker), Interreg (SKiN-HUID), and Fonds voor Wetenschappelijk Onderzoek Vlaanderen (#G.0929.16N). J.F. was supported by the Swedish Research Council. A.W.L. was supported by the OHSU Knight Cancer Center Support grant NIH P30-CA069533, the Department of Defense Peer Reviewed Cancer Research Program (W81XWH-15-1-0348), V Foundation for Cancer Research (V2015-024), and the Cancer Research Institute and Melanoma Research Alliance. Funding Information: We thank G. Bervoets for excellent technical assistance and Prof. G. Ghanem for the MM lines. M. Stas and V. Boecxstaens provided samples for the PDX models. PDX experiments were developed by TRACE with the assistance of E. Leucci, L. Rizzotto, F. Amant, E. Hermans, D. Thomas, E. Gomm? and K. Crevits. FACS was performed by P.A. Penttila and C. Nkama. The TruSight26 analysis was performed by S. Vander Borght. We thank the University Research Priority Program in translational cancer research for access to the melanoma material. D. Nittner and L. Omodho provided histology support. F.R. received a fellowship from the Omics/Marie Curie@VIB. This work was supported by KUL GOA (#14/012), VLK (Vlaamse Liga tegen Kanker), Interreg (SKiN-HUID), and Fonds voor Wetenschappelijk Onderzoek Vlaanderen (#G.0929.16N). J.F. was supported by the Swedish Research Council. A.W.L. was supported by the OHSU Knight Cancer Center Support grant NIH P30-CA069533, the Department of Defense Peer Reviewed Cancer Research Program (W81XWH-15-1-0348), V Foundation for Cancer Research (V2015-024), and the Cancer Research Institute and Melanoma Research Alliance. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = aug,
day = "9",
doi = "10.1016/j.cell.2018.06.025",
language = "English (US)",
volume = "174",
pages = "843--855.e19",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}