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

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.

AMPK–mTOR–Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells

“…For cultured cells and tissue sections, nucleus area measurement was performed with Zen and Image J software as described previously ( 26 ). If the nuclear area exceeded 350 μm 2 in size, it was defined as a PGCC.…”

Polyploid giant cancer cells and cancer progression

“…Overexpression of PRL3 uncouples the cell cycle from DNA replication and induces PGCCs formation, which contributes to a significant increase in the ploidy of progeny cells rather than an increase in cell number. Moreover, overexpressed PRL3 inhibits the ataxia telangiectasia mutated (ATM)-related DNA damage, thereby allowing PGCCs to survive ( Thura et al, 2021 ). ATM is a kind of kinases that activates cell cycle checkpoints after DNA damage.…”

“…PRL3 can induce a stem cell-like transcriptional program and promote cancer growth and survival ( Zhou et al, 2017 ). Overexpression of PRL3 makes cells insensitive to DNA damage by inhibiting the ATM-mediated DNA damage, and helps them escape apoptosis under long-term genotoxic stress ( Thura et al, 2021 ). PRL3-zumab blocks the role of PGCCs in tumors, by targeting the inhibition of PRL3, as an adjuvant immunotherapy.…”

“…Mitosis-independent PGCCs retreat from the therapy-induced senescence by means of depolyploidization, and generate PDCs for tumor propagation and disease recurrence ( Liang et al, 2007 ; Al-Aidaroos and Zeng, 2010 ). PRL3-zumab targets “dormant” tumor cells, by inactivating classical chemo-resistant and residual PGCCs with self-renewal ( Thura et al, 2021 ). Recently, PRL3-zumab was rapidly approved by the US Food and Drug Administration and the National Medical Products Administration for Phase II IND trials of solid PRL3 cancer in the United States of America.…”

The double lives of phosphatases of regenerating liver: A structural view of their catalytic and noncatalytic activities

“…This unconventional approach is based on the presence of PRL-3 antigens on the cell surface, which leads to antibody-dependent cytotoxicity or phagocytosis of the tumor cells. The humanized antibody, PRL3-zumab, reduced tumor relapse in an animal model and has been approved for Phase 2 clinical trials against solid tumors in Singapore, United States, and China ( 83 ).…”