PRL3 induces polyploid giant cancer cells eliminated by PRL3-zumab to reduce tumor relapse

Min Thura,Qiancheng Xiong,Ke Guo,Zu Ye,Koon Hwee Ang,Jun Yi Ong,Qi Zeng,Abdul Qader Al-Aidaroos,Abhishek Gupta,Jie Li

doi:10.1038/s42003-021-02449-8

Abstract

PRL3, a unique oncotarget, is specifically overexpressed in 80.6% of cancers. In 2003, we reported that PRL3 promotes cell migration, invasion, and metastasis. Herein, firstly, we show that PRL3 induces Polyploid Giant Cancer Cells (PGCCs) formation. PGCCs constitute stem cell-like pools to facilitate cell survival, chemo-resistance, and tumor relapse. The correlations between PRL3 overexpression and PGCCs attributes raised possibilities that PRL3 could be involved in PGCCs formation. Secondly, we show that PRL3+ PGCCs co-express the embryonic stem cell markers SOX2 and OCT4 and arise mainly due to incomplete cytokinesis despite extensive DNA damage. Thirdly, we reveal that PRL3+ PGCCs tolerate prolonged chemotherapy-induced genotoxic stress via suppression of the pro-apoptotic ATM DNA damage-signaling pathway. Fourthly, we demonstrated PRL3-zumab, a First-in-Class humanized antibody drug against PRL3 oncotarget, could reduce tumor relapse in ‘tumor removal’ animal model. Finally, we confirmed that PGCCs were enriched in relapse tumors versus primary tumors. PRL3-zumab has been approved for Phase 2 clinical trials in Singapore, US, and China to block all solid tumors. This study further showed PRL3-zumab could potentially serve an ‘Adjuvant Immunotherapy’ after tumor removal surgery to eliminate PRL3+ PGCC stem-like cells, preventing metastasis and relapse.

Highlights

Phosphatase of regenerating liver 3 (PRL3), a unique oncotarget, is overexpressed in 80.6% of cancers
We show here that PRL3 overexpression induces the formation of Polyploid Giant Cancer Cells (PGCCs), which displayed marked resistance to cisplatin chemotherapy by inhibiting proapoptotic DNA damage signaling pathways, enhancing cancer cell survival
To validate whether PRL3-induced PGCCs possess stem cell characteristics, we investigated the expression of SOX2 and OCT4, two well-established embryonic stem cell markers[27,28]

Summary

Introduction

PRL3, a unique oncotarget, is overexpressed in 80.6% of cancers. In 2003, we reported that PRL3 promotes cell migration, invasion, and metastasis. PGCCs constitute stem cell-like pools to facilitate cell survival, chemo-resistance, and tumor relapse. This study further showed PRL3-zumab could potentially serve an ‘Adjuvant Immunotherapy’ after tumor removal surgery to eliminate PRL3+ PGCC stem-like cells, preventing metastasis and relapse. PGCCs constitute stem cell-like pools facilitating cancer cell survival, therapy resistance, and tumor relapse. PGCCs was reported to provide a survival advantage to hypoxic tumor cells by generating erythroid cells and inducing neoangiogenesis via vasculogenic mimicry[20] These striking similarities between PRL3 overexpression and PGCCs attributes raised the intriguing possibility that PRL3 could be involved in PGCC formation. We show here that PRL3 overexpression induces the formation of PGCCs, which displayed marked resistance to cisplatin chemotherapy by inhibiting proapoptotic DNA damage signaling pathways, enhancing cancer cell survival. We anticipate PRL3-zumab could act as ‘Double Swords’: inhibiting tumor growth and preventing cancer relapse to overcome cancer metastasis

Methods

Results

Conclusion