Toward Minimal Residual Disease-Directed Therapy in Melanoma

Florian Rambow, Aljosja Rogiers, Oskar Marin-Bejar, Sara Aibar, Julia Femel, Michael Dewaele, Panagiotis Karras, Daniel Brown, Young Hwan Chang, Maria Debiec-Rychter, Carmen Adriaens, Enrico Radaelli, Pascal Wolter, Oliver Bechter, Reinhard Dummer, Mitchell Levesque, Adriano Piris, Dennie T. Frederick, Genevieve Boland, Keith T. FlahertyJoost van den Oord, Thierry Voet, Stein Aerts, Amanda Lund, Jean Christophe Marine

Research output: Contribution to journalArticle

63 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)843-855.e19
JournalCell
Volume174
Issue number4
DOIs
StatePublished - Aug 9 2018

    Fingerprint

Keywords

  • cutaneous melanoma
  • drug tolerance
  • gene regulatory networks
  • RXR signaling
  • single cell transcriptomics
  • targeted therapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Rambow, F., Rogiers, A., Marin-Bejar, O., Aibar, S., Femel, J., Dewaele, M., Karras, P., Brown, D., Chang, Y. H., Debiec-Rychter, M., Adriaens, C., Radaelli, E., Wolter, P., Bechter, O., Dummer, R., Levesque, M., Piris, A., Frederick, D. T., Boland, G., ... Marine, J. C. (2018). Toward Minimal Residual Disease-Directed Therapy in Melanoma. Cell, 174(4), 843-855.e19. https://doi.org/10.1016/j.cell.2018.06.025