Single-cell transcriptomics of NRAS-mutated melanoma transitioning to drug resistance reveals P2RX7 as an indicator of early drug response
Tijana Randic,
Stefano Magni,
Demetra Philippidou,
Christiane Margue,
Kamil Grzyb,
Jasmin Renate Preis,
Joanna Patrycja Wroblewska,
Petr V. Nazarov,
Michel Mittelbronn,
Katrin B.M. Frauenknecht,
Alexander Skupin,
Stephanie Kreis
Affiliations
Tijana Randic
Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg
Stefano Magni
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg
Demetra Philippidou
Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg
Christiane Margue
Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg
Kamil Grzyb
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg
Jasmin Renate Preis
Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg
Joanna Patrycja Wroblewska
Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg
Petr V. Nazarov
Data Integration and Analysis Unit (DIA), Luxembourg Institute of Health, 1A-B, Rue Thomas Edison, 1445 Strassen, Luxembourg; Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, 6A, Rue Nicolas-Ernest Barblé, 1210 Luxembourg, Luxembourg
Michel Mittelbronn
Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg; Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, 6A, Rue Nicolas-Ernest Barblé, 1210 Luxembourg, Luxembourg; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg
Katrin B.M. Frauenknecht
National Center of Pathology (NCP), Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg; Luxembourg Center of Neuropathology (LCNP), Dudelange, Luxembourg
Alexander Skupin
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg; Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, 6A, Rue Nicolas-Ernest Barblé, 1210 Luxembourg, Luxembourg; Department of Neuroscience, University of California San Diego, 9500 Gillman Drive, La Jolla, CA 92093, USA
Stephanie Kreis
Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg; Corresponding author
Summary: Treatment options for patients with NRAS-mutant melanoma are limited and lack an efficient targeted drug combination that significantly increases overall and progression-free survival. In addition, targeted therapy success is hampered by the inevitable emergence of drug resistance. A thorough understanding of the molecular processes driving cancer cells’ escape mechanisms is crucial to tailor more efficient follow-up therapies. We performed single-cell RNA sequencing of NRAS-mutant melanoma treated with MEK1/2 plus CDK4/6 inhibitors to decipher transcriptional transitions during the development of drug resistance. Cell lines resuming full proliferation (FACs [fast-adapting cells]) and cells that became senescent (SACs [slow-adapting cells]) over prolonged treatment were identified. The early drug response was characterized by transitional states involving increased ion signaling, driven by upregulation of the ATP-gated ion channel P2RX7. P2RX7 activation was associated with improved therapy responses and, in combination with targeted drugs, could contribute to the delayed onset of acquired resistance in NRAS-mutant melanoma.
