2. Academic Validation
  3. Toward Minimal Residual Disease-Directed Therapy in Melanoma

Toward Minimal Residual Disease-Directed Therapy in Melanoma

  • Cell. 2018 Aug 9;174(4):843-855.e19. doi: 10.1016/j.cell.2018.06.025.
Florian Rambow 1,  Aljosja Rogiers 1,  Oskar Marin-Bejar 1,  Sara Aibar 2,  Julia Femel 3,  Michael Dewaele 1,  Panagiotis Karras 1,  Daniel Brown 4,  Young Hwan Chang 5,  Maria Debiec-Rychter 6,  Carmen Adriaens 1,  Enrico Radaelli 7,  Pascal Wolter 8,  Oliver Bechter 8,  Reinhard Dummer 9,  Mitchell Levesque 9,  Adriano Piris 10,  Dennie T Frederick 10,  Genevieve Boland 10,  Keith T Flaherty 11,  Joost van den Oord 12,  Thierry Voet 4,  Stein Aerts 2,  Amanda W Lund 3,  Jean-Christophe Marine 13
Affiliations

Affiliations

  • 1 Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
  • 2 Laboratory of Computational Biology, VIB Center for Brain & Disease Research, KU Leuven, Leuven, Belgium; Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • 3 Department of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
  • 4 Laboratory of reproductive genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • 5 Department of Biomedical Engineering, Oregon Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, OR, USA.
  • 6 Laboratory for Genetics of Malignant Disorders, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • 7 Comparative Pathology Core, University of Pennsylvania, Department of Pathobiology, Philadelphia, PA, USA.
  • 8 Department of General Medical Oncology, UZ Leuven, Leuven, Belgium.
  • 9 Department of Dermatology, University of Zürich Hospital, Zürich, Switzerland.
  • 10 Department of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA.
  • 11 Department of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA.
  • 12 Laboratory of Translational Cell and Tissue Research, Department of Pathology, UZ Leuven, Leuven, Belgium.
  • 13 Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: jeanchristophe.marine@kuleuven.vib.be.
PMID: 30017245 DOI: 10.1016/j.cell.2018.06.025
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.

Keywords

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

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