Issue No. 35, January 2021
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine, VCU and external experts focusing on important medically-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.     
PLK1 induces chromosomal instability and overrides cell cycle checkpoints to drive tumorigenesis.
 
A recent discovery published in Cancer Research by Dr. Fu and collaborators have demonstrated the roles of PLK1 as a potent proto-oncogene and a chromosomal instability (CIN) gene and provides valuable insights into PLK1’s oncogenic action, which will greatly facilitate the development of more effective and targeted treatment regimens across the landscape of PLK1-overexpressing and CIN-positive cancers.

  • Using a Plk1 transgenic mouse model, the investigators have demonstrated that high Plk1 levels are a driving force for various types of spontaneous tumors.

  • Increased Plk1 expression promotes supernumerary centrosomes and mitotic aberrations, resulting in chromosomal instability.

  • PLK1 overrides cell cycle checkpoints, which allows cells to tolerate genomic chaos and continue proliferating.

  • Increased Plk1 expression is causally linked to the acquisition of aberrant karyotypes in cancer cells and may contribute to chromosomal heterogeneity in tumors.

  • Higher Plk1 expression is positively associated with an increase in genome-wide copy number alterations in multiple human cancers.

  • These findings highlight potential therapeutic opportunities for CIN-positive cancers.

Polo-like kinase 1 (PLK1), an essential cell cycle regulator, is frequently overexpressed in various human cancers. Accumulating evidence suggests that PLK1 overexpression may drive tumorigenesis in humans. However, an in vivo animal model providing compelling confirmation of PLK1 as a proto-oncogene and facilitating elucidation of its oncogenic function has been lacking. New research from Dr. Fu and collaborators published in Cancer Research provides direct evidence that Plk1 has potent oncogenic properties, driving malignant transformation and spontaneous tumorigenesis, which is also strongly supported by clinical studies in humans. 
 
Using a Plk1 transgenic mouse model, the investigators show that enhanced Plk1 expression is sufficient to drive the formation of spontaneous tumors (including lymphomas, carcinomas, and sarcomas) in multiple organs (Figure 1 A and B). Increased Plk1 expression drives CIN by promoting the formation of supernumerary centrosomes and numerous mitotic errors, including chromosome misalignment, chromosome mis-segregation, and cytokinesis failure, leading to genomic chaos and the formation of giant multinucleated cells and micronucleated cells. Additionally, increased Plk1 expression overrides cell cycle checkpoints, including the spindle assembly checkpoint (SAC) and the DNA-damage checkpoint, which causes robust inactivation of genomic surveillance mechanisms, allowing cells to tolerate CIN and continue to proliferate (Figure 1C). In addition, meta-analysis of publicly available genome-wide copy number alterations (CNAs) and gene expression datasets revealed that higher PLK1 expression is significantly correlated with an increase in genome-wide segment copy number and associates with poorer prognosis in multiple human cancers, which provide clinical evidence that further substantiates the role of PLK1 overexpression in CIN and tumor development. Consequently, these findings establish, for the first time, the roles of PLK1 as a potent proto-oncogene and a CIN gene. More importantly, they provide valuable insights into PLK1’s oncogenic action, which will greatly facilitate the development of more effective and targeted treatment regimens across the landscape of PLK1-overexpressing and CIN-positive cancers.
Figure 1. PLK1 induces chromosomal instability and overrides cell cycle checkpoints to drive tumorigenesis. (A) (Left) Mouse cohort information, between 0 to 24 months. (Right) Survival curves for WT, TA/+, and TA/TA mice (TA/+ vs TA/TA: p = 0.0013, log-rank test). (B) (Left) Spontaneous tumor incidence in WT, TA/+, and TA/TA mice. (***: p < 0.001, Chi-squared test) (Right) Distinct neoplasm incidence in transgenic mice. (C) Mechanisms by which PLK1 drives tumorigenesis in humans.
Publication:

Gheghiani L, Wang L, Zhang Y, Moore XTR, Zhang J, Smith SC, Tian Y, Wang L, Turner K, Jackson-Cook CK, Mukhopadhyay ND, Fu Z. PLK1 induces chromosomal instability and overrides cell cycle checkpoints to drive tumorigenesis. Cancer Res. 2020 Dec 29; canres.1377.2020. PMID: 33376114 DOI: 10.1158/0008-5472.CAN-20-1377
 
About the Investigators: Zheng Fu, PhD, the corresponding author, is an Associate Professor in the Department of Human and Molecular Genetics (HMG) at Virginia Commonwealth University (VCU) School of Medicine, and a member of the VIMM and the MCC. Dr. Lilia Gheghiani, is a postdoc in the Department of HMG, the first author of this paper, and performed much of the biological and animal work. The present study was supported by US ACS RSG 127626-RSG-15-005-01-CCG and NIH R01 CA191002. Histological staining was performed in part by the VCU Cancer Mouse Models Core Laboratory, and microscopy was performed at the VCU Massey Cancer Center (MCC) Microscopy Core Facility. Both Cores are supported, in part, by the MCC NIH-NCI Cancer Center Support Grant P30 CA016059.