Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase

Area of Science:

• Developmental Biology
• Cancer Biology
• Cell Signaling

Background:

• Matriptase 1 (ST14), a serine protease, exhibits dual roles in cancer, acting as both an oncogene and a tumor suppressor.
• The precise mechanisms underlying Matriptase's opposing functions in vivo remain incompletely understood, particularly in early development.

Purpose of the Study:

• To elucidate the dual role of Matriptase 1 (ST14) in epidermal carcinogenesis using zebrafish models.
• To identify key molecular mediators, including phospholipase D (PLD), involved in Matriptase's context-dependent functions.
• To explore therapeutic strategies targeting Matriptase-mediated pathways for cancer treatment.

Main Methods:

• Utilized zebrafish loss-of-function mutants for Matriptase inhibitor Hai1a (Spint1a) to study epidermal development.
• Investigated the roles of epidermal growth factor receptor (EGFR), phospholipase D (PLD), and sphingosine-1-phosphate (S1P) signaling.
• Assessed the effects of PLD inhibitors and S1P in rescuing lethal Hai1a mutant phenotypes.

Main Results:

• Hai1a (Spint1a) deficiency in zebrafish embryos led to epidermal hyperplasia and tumor-suppressive apical cell extrusions involving entosis.
• Matriptase's opposing effects were dependent on EGFR and PLD, which modulated mTORC1-driven proliferation and S1P-driven entosis/extrusion.
• Combined inhibition of PLD and S1P administration rescued lethal Hai1a mutant phenotypes, indicating a critical role for this pathway.

Conclusions:

• This study reveals the intricate mechanisms behind Matriptase 1's dual function in vivo, highlighting its context-dependent oncogenic and tumor-suppressive activities.
• Phospholipase D (PLD) and sphingosine-1-phosphate (S1P) signaling are critical mediators of these opposing functions.
• Combinatorial therapeutic approaches targeting PLD and S1P pathways show promise for treating cancers involving similar Matriptase-driven mechanisms.