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PRL3 induces polypoid giant cancer cells eliminated by PRL3-zumab to reduce tumor relapse
Min Thura1, Zu Ye2, Abdul Qader Al-Aidaroos1
1Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
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.
Insights
Protein tyrosine phosphatase like 13 (PRL3) drives cancer stem cell formation and chemoresistance. Targeting PRL3 with PRL3-zumab antibody therapy may prevent tumor relapse and metastasis by eliminating these cancer stem cells.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Therapeutics
Background:
- Protein tyrosine phosphatase like 13 (PRL3) is overexpressed in over 80% of cancers and promotes metastasis.
- Polyploid Giant Cancer Cells (PGCCs) are stem-like cells implicated in tumor survival, chemoresistance, and relapse.
Purpose of the Study:
- To investigate the role of PRL3 in PGCC formation and characteristics.
- To evaluate the efficacy of the humanized antibody PRL3-zumab in preventing tumor relapse.
Main Methods:
- Analysis of PRL3 expression and PGCC markers (SOX2, OCT4) in cancer cells.
- Assessment of DNA damage response and apoptosis pathways in PRL3+ PGCCs.
- Evaluation of PRL3-zumab efficacy in a 'tumor removal' animal model.
- Comparison of PGCC enrichment in primary versus relapse tumors.
Main Results:
- PRL3 overexpression induces PGCC formation through incomplete cytokinesis.
- PRL3+ PGCCs exhibit stem cell markers and resist chemotherapy by suppressing ATM signaling.
- PRL3-zumab reduced tumor relapse in animal models.
- PGCCs are significantly enriched in relapse tumors.
Conclusions:
- PRL3 plays a critical role in generating and maintaining cancer stem-like cells (PGCCs) that drive tumor relapse.
- PRL3-zumab demonstrates potential as a therapeutic agent to eliminate PRL3+ PGCCs and prevent cancer recurrence.
- PRL3-zumab may serve as an adjuvant immunotherapy post-surgery to eradicate residual disease and prevent metastasis.
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