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 to cutaneous SCC (cSCC) and identified MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids enabled malignant transformation through increased expression of the receptor tyrosine kinase rearranged during transfection (RET). In addition to transcriptional upregulation of RET, MAB21L4 deletion preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. Both genetic disruption of RET or selective RET inhibition with BLU-667 (pralsetinib) suppressed tumorigenesis in SCC organoids and in vivo tumors while inducing concomitant differentiation. Our results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC.
Statement of Significance Few targeted therapies are available to individuals with cSCC who seek or require non-surgical management. Our study demonstrates that downregulation of RET is required for epithelial differentiation and opposes carcinogenesis in cSCC as well as SCC arising from other epithelial tissues.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Financial support: CSL is the recipient of a Clinical Scientist Development Award from the Doris Duke Charitable Foundation (#2018094), a Kimmel Scholar Award from the Sidney Kimmel Foundation, and a Milstein Research Scholar Award from the American Skin Association. Additionally, she is mentored and financially supported by Stanford’s SPARK Translational Research Program and the LEO Foundation. AS is supported by an International Postdoctoral Grant from the Swedish Research Council (Vetenskapsrådet-VR). CT received a Stanford Dean’s Postdoctoral Fellowship. VLP is the recipient of K01 AR070895 from NIH/NIAMS.
The authors declare no potential conflicts of interest.
