Emerging roles for the GPI-anchored tumor suppressor OPCML in cancers

Abstract

OPCML is a highly conserved glycosyl phosphatidylinositol (GPI)-anchored protein belonging to the IgLON family of cell adhesion molecules. OPCML functions as a tumor suppressor and is silenced in over 80% of ovarian cancers by loss of heterozygosity and by epigenetic mechanisms. OPCML inactivation is also observed in many other cancers suggesting a conservation of tumor suppressor function. Although epigenetic silencing and subsequent loss of OPCML expression correlate with poor progression-free and overall patient survival, its mechanism of action is only starting to be fully elucidated. Recent discoveries have demonstrated that OPCML exerts its tumor suppressor effect by inhibiting several cancer hallmark phenotypes in vitro and abrogating tumorigenesis in vivo, by downregulating/inactivating a specific spectrum of Receptor Tyrosine Kinases (RTKs), including EphA2, FGFR1, FGFR3, HER2, HER4, and AXL. This modulation of RTKs can also sensitize ovarian and breast cancers to lapatinib, erlotinib, and anti-AXL therapies. Furthermore, OPCML has also been shown to function in synergy with the tumor suppressor phosphatase PTPRG to inactivate pro-metastatic RTKs such as AXL. Recently, the identification of inactivating point mutations and the elucidation of the crystal structure of OPCML have provided valuable insights into its structure-function relationships, giving rise to its potential as an anti-cancer therapeutic.

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Fig. 1: Domain organization and structural biology of IgLON family members.
Fig. 2: OPCML modulation of oncogenic pathways.
Fig. 3: Cancer-associated mutations in OPCML.

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Acknowledgements

JA, EZ, JRB, HG, and CR received no financial assistance.

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Correspondence to Chiara Recchi.

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HG has ownership interest (including patents) to develop OPCML-based therapeutics. He is also Chief Medical Officer at BergenBio (producer of the AXL inhibitor BGB324). The remaining authors declare that they have no conflict of interest.

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Antony, J., Zanini, E., Birtley, J.R. et al. Emerging roles for the GPI-anchored tumor suppressor OPCML in cancers. Cancer Gene Ther (2020). https://doi.org/10.1038/s41417-020-0187-6

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