TY - JOUR
T1 - A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma
AU - Gureghian, Vincent
AU - Herbst, Hailee
AU - Kozar, Ines
AU - Mihajlovic, Katarina
AU - Malod-Dognin, Noël
AU - Ceddia, Gaia
AU - Angeli, Cristian
AU - Margue, Christiane
AU - Randic, Tijana
AU - Philippidou, Demetra
AU - Nomigni, Milène Tetsi
AU - Hemedan, Ahmed
AU - Tranchevent, Leon Charles
AU - Longworth, Joseph
AU - Bauer, Mark
AU - Badkas, Apurva
AU - Gaigneaux, Anthoula
AU - Muller, Arnaud
AU - Ostaszewski, Marek
AU - Tolle, Fabrice
AU - Pržulj, Nataša
AU - Kreis, Stephanie
N1 - Funding Information:
VG is supported by the Luxembourg National Research Fond (FNR) PRIDE DTU CanBIO [grant reference: 21/16763386]. TR is supported by the FNR PRIDE DTU CriTiCS [grant reference: 10907093]. Project-related work performed by VG, HH, CM, DP, MTN, MB, AG, FT and SK were also supported by the University of Luxembourg and the Fondation Cancer, Luxembourg (grant “SecMelPro”). KM and NP are supported by funding from the European Union’s EU Framework Programme for Research and Innovation Horizon 2020, Innovative Training Networks (MSCA-ITN-2019), funded under EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions, Grant Agreement No 860895. KM, NMD, GC and NP are supported by funding from the European Research Council (ERC) Consolidator Grant 770827. NP is also supported by funding from the Spanish State Research Agency AEI 10.13039/501100011033 grant number PID2019-105500GB-I00.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/10
Y1 - 2023/10
N2 - Therapy Induced Senescence (TIS) leads to sustained growth arrest of cancer cells. The associated cytostasis has been shown to be reversible and cells escaping senescence further enhance the aggressiveness of cancers. Chemicals specifically targeting senescent cells, so-called senolytics, constitute a promising avenue for improved cancer treatment in combination with targeted therapies. Understanding how cancer cells evade senescence is needed to optimise the clinical benefits of this therapeutic approach. Here we characterised the response of three different NRAS mutant melanoma cell lines to a combination of CDK4/6 and MEK inhibitors over 33 days. Transcriptomic data show that all cell lines trigger a senescence programme coupled with strong induction of interferons. Kinome profiling revealed the activation of Receptor Tyrosine Kinases (RTKs) and enriched downstream signaling of neurotrophin, ErbB and insulin pathways. Characterisation of the miRNA interactome associates miR-211-5p with resistant phenotypes. Finally, iCell-based integration of bulk and single-cell RNA-seq data identifies biological processes perturbed during senescence and predicts 90 new genes involved in its escape. Overall, our data associate insulin signaling with persistence of a senescent phenotype and suggest a new role for interferon gamma in senescence escape through the induction of EMT and the activation of ERK5 signaling.
AB - Therapy Induced Senescence (TIS) leads to sustained growth arrest of cancer cells. The associated cytostasis has been shown to be reversible and cells escaping senescence further enhance the aggressiveness of cancers. Chemicals specifically targeting senescent cells, so-called senolytics, constitute a promising avenue for improved cancer treatment in combination with targeted therapies. Understanding how cancer cells evade senescence is needed to optimise the clinical benefits of this therapeutic approach. Here we characterised the response of three different NRAS mutant melanoma cell lines to a combination of CDK4/6 and MEK inhibitors over 33 days. Transcriptomic data show that all cell lines trigger a senescence programme coupled with strong induction of interferons. Kinome profiling revealed the activation of Receptor Tyrosine Kinases (RTKs) and enriched downstream signaling of neurotrophin, ErbB and insulin pathways. Characterisation of the miRNA interactome associates miR-211-5p with resistant phenotypes. Finally, iCell-based integration of bulk and single-cell RNA-seq data identifies biological processes perturbed during senescence and predicts 90 new genes involved in its escape. Overall, our data associate insulin signaling with persistence of a senescent phenotype and suggest a new role for interferon gamma in senescence escape through the induction of EMT and the activation of ERK5 signaling.
UR - http://www.scopus.com/inward/record.url?scp=85164201373&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37420093
U2 - 10.1038/s41417-023-00640-z
DO - 10.1038/s41417-023-00640-z
M3 - Article
C2 - 37420093
AN - SCOPUS:85164201373
SN - 0929-1903
VL - 30
SP - 1330
EP - 1345
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
IS - 10
ER -