MAB21L4 Deficiency Drives Squamous Cell Carcinoma via Activation of RET

Abstract

Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. In SCC organoids and in vivo tumor models, genetic disruption of RET or selective inhibition of RET with BLU-667 (pralsetinib) suppressed SCC growth while inducing concomitant differentiation. Overall, loss of MAB21L4 early during SCC development blocks differentiation by increasing RET expression. These results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC. Significance: Downregulation of RET mediated by MAB21L4–CacyBP interaction is required to induce epidermal differentiation and suppress carcinogenesis, suggesting RET inhibition as a potential therapeutic approach in squamous cell carcinoma.

Gene expression landscape of cutaneous squamous cell carcinoma progression

“…Pathways previously implicated in SCC, such as interferon signaling, EMT, and lipid metabolism (6,32,(56)(57)(58), were identified by enrichment analysis and overlapped with pathways found from individual-study analysis (Figure 3d). Recent work by our group suggests RET activation plays a role in SCC pathogenesis and demonstrates the therapeutic potential of RET inhibition in this malignancy (30). As further support of these findings, consensus DEGs included the RET ligand ARTN as well as RET biomarkers DUSP6 and SPRY4 (59), which were increased in the progression from NS to SCC in the combined cohort (Figure S3b).…”

“…Recent work by our group suggests RET activation plays a role in SCC pathogenesis and demonstrates the therapeutic potential of RET inhibition in this malignancy (30). As further support of these findings, consensus DEGs included the RET ligand ARTN as well as RET biomarkers DUSP6 and SPRY4 (59), which were increased in the progression from NS to SCC in the combined cohort ( Figure S3b ).…”

“…A search for publicly available RNA-Seq samples of SCC, AK, IEC, KA, and/or NS identified 12 studies published in 2016-2023 with an average of 32 samples that met our initial inclusion criteria (Table 1) (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Raw FASTQ data from these studies were downloaded and uniformly processed using STAR (46) for sequence alignment and RSEM (47) for read quantification; reads were aligned to the GENCODE v38 reference.…”