The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer.
3D
AKT
ALK
ALKAL2
CMS1
Colon Cancer therapy
Signalling
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
29 Mar 2022
29 Mar 2022
Historique:
received:
21
09
2021
accepted:
03
03
2022
entrez:
30
3
2022
pubmed:
31
3
2022
medline:
5
4
2022
Statut:
epublish
Résumé
In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). In this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use. ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo. Collectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.
Sections du résumé
BACKGROUND
BACKGROUND
In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs).
METHODS
METHODS
In this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use.
RESULTS
RESULTS
ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo.
CONCLUSIONS
CONCLUSIONS
Collectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.
Identifiants
pubmed: 35351152
doi: 10.1186/s13046-022-02309-1
pii: 10.1186/s13046-022-02309-1
pmc: PMC8962179
doi:
Substances chimiques
ALKAL2 protein, human
0
Cytokines
0
Ligands
0
Anaplastic Lymphoma Kinase
EC 2.7.10.1
Types de publication
Journal Article
Meta-Analysis
Langues
eng
Sous-ensembles de citation
IM
Pagination
113Subventions
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : 2017TATYMP_002
Organisme : Regione Emilia-Romagna
ID : Bando Regionale "Alte Competenze per la Ricerca e il Trasferimento Tecnologico" 2018
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : AIRC fellowship for Italy
Organisme : Fondazione Cariplo
ID : Cariplo 2017-0800
Organisme : Università di Bologna
ID : eDIMES Lab funds
Informations de copyright
© 2022. The Author(s).
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