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 language | English (US) |
|---|---|
| Pages (from-to) | 843-855.e19 |
| Journal | Cell |
| Volume | 174 |
| Issue number | 4 |
| DOIs | |
| State | Published - Aug 9 2018 |
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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
Toward Minimal Residual Disease-Directed Therapy in Melanoma. / Rambow, Florian; Rogiers, Aljosja; Marin-Bejar, Oskar; Aibar, Sara; Femel, Julia; Dewaele, Michael; Karras, Panagiotis; Brown, Daniel; Chang, Young Hwan; Debiec-Rychter, Maria; Adriaens, Carmen; Radaelli, Enrico; Wolter, Pascal; Bechter, Oliver; Dummer, Reinhard; Levesque, Mitchell; Piris, Adriano; Frederick, Dennie T.; Boland, Genevieve; Flaherty, Keith T.; van den Oord, Joost; Voet, Thierry; Aerts, Stein; Lund, Amanda; Marine, Jean Christophe.
In: Cell, Vol. 174, No. 4, 09.08.2018, p. 843-855.e19.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Toward Minimal Residual Disease-Directed Therapy in Melanoma
AU - Rambow, Florian
AU - Rogiers, Aljosja
AU - Marin-Bejar, Oskar
AU - Aibar, Sara
AU - Femel, Julia
AU - Dewaele, Michael
AU - Karras, Panagiotis
AU - Brown, Daniel
AU - Chang, Young Hwan
AU - Debiec-Rychter, Maria
AU - Adriaens, Carmen
AU - Radaelli, Enrico
AU - Wolter, Pascal
AU - Bechter, Oliver
AU - Dummer, Reinhard
AU - Levesque, Mitchell
AU - Piris, Adriano
AU - Frederick, Dennie T.
AU - Boland, Genevieve
AU - Flaherty, Keith T.
AU - van den Oord, Joost
AU - Voet, Thierry
AU - Aerts, Stein
AU - Lund, Amanda
AU - Marine, Jean Christophe
PY - 2018/8/9
Y1 - 2018/8/9
N2 - 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.
AB - 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.
KW - cutaneous melanoma
KW - drug tolerance
KW - gene regulatory networks
KW - RXR signaling
KW - single cell transcriptomics
KW - targeted therapy
UR - http://www.scopus.com/inward/record.url?scp=85049472211&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049472211&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.06.025
DO - 10.1016/j.cell.2018.06.025
M3 - Article
VL - 174
SP - 843-855.e19
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
ER -