The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer

Abstract

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 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 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 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.

Genome-wide screening for differentially methylated long noncoding RNAs identifies LIFR-AS1 as an epigenetically regulated lncRNA that inhibits the progression of colorectal cancer

“…Colorectal cancer (CRC) is the third most common malignancy and the second highest cancer-related cause of death in the world [ 1 ]. CRC is caused by the accumulation of multiple genetic and epigenetic alterations in the genome [ 2 , 3 ]. Over the past decade, research has focused on better understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA and long noncoding RNA (lncRNA) deregulation, to identify prognostic and predictive factors for cancer [ 3 ].…”

ALK signaling drives tumorigenicity and chemoresistance of pancreatic ductal adenocarcinoma cells

“…Nevertheless, further bioinformatic analyses of transcriptomic datasets supported our initial results in vitro . Indeed, we were able to link the mRNA expression of both ALK and an ALK overexpression (OE) signature previously described [23] with pathways related with CSCs in PDAC patients, such as epithelial-to-mesenchymal transition (EMT), drug metabolism and stemness ( Fig. 1D, 1E ).…”

“…1E ) [22] . On the other hand, besides pathways related to ALK downstream signaling such as K-Ras or JAK/STAT, ALK HIGH samples also showed enrichment of an ALK overexpression (OE) gene signature described in breast cancer cells [23] ( Fig. 1E ).…”

“…[22] and Mazzeschi et al . [23] , respectively. ALK mutational status was assessed using the webserver cBioPortal (Pancreas UTSW, Pancreas TCGA PanCan 2018, Pancreas TCGA, Pancreas ICGC and Pancreas QCMG 2016 project datasets; https://www.cbioportal.org.…”

Pharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma

“…The GSEA module of the GenePattern suite from the Broad Institute was used with 1000 permutations and FDR < 25 % was considered statistically significant. The signatures for stemness and ALK overexpression (OE) were previously described in Ai et al [22] and Mazzeschi et al [23], respectively. ALK mutational status was assessed using the webserver cBioPortal (Pancreas UTSW, Pancreas TCGA PanCan 2018, Pancreas TCGA, Pancreas ICGC and Pancreas QCMG 2016 project datasets; https://www.cbioportal.org) [24].…”