title: Linking genomic reorganization to tumor initiation via the giant cell cycle.
abstract: To investigate the mechanisms underlying our recent paradoxical finding that mitotically incapacitated and genomically unstable polyploid giant cancer cells (PGCCs) are capable of tumor initiation, we labeled ovarian cancer cells with α-tubulin fused to green fluorescent protein, histone-2B fused to red fluorescent protein and FUCCI (fluorescent ubiquitination cell cycle indicator), and tracked the spatial and time-dependent change in spindle and chromosomal dynamics of PGCCs using live-cell fluorescence time-lapse recording. We found that single-dose (500 nm) treatment with paclitaxel paradoxically initiated endoreplication to form PGCCs after massive cell death. The resulting PGCCs continued self-renewal via endoreplication and further divided by nuclear budding or fragmentation; the small daughter nuclei then acquired cytoplasm, split off from the giant mother cells and acquired competency in mitosis. FUCCI showed that PGCCs divided via truncated endoreplication cell cycle (endocycle or endomitosis). Confocal microscopy showed that PGCCs had pronounced nuclear fragmentation and lacked expression of key mitotic proteins. PGCC-derived daughter cells were capable of long-term proliferation and acquired numerous new genome/chromosome alterations demonstrated by spectral karyotyping. These data prompt us to conceptualize a giant cell cycle composed of four distinct but overlapping phases, initiation, self-renewal, termination and stability. The giant cell cycle may represent a fundamental cellular mechanism to initiate genomic reorganization to generate new tumor-initiating cells in response to chemotherapy-induced stress and contributes to disease relapse.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Niu
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: I
authors.initials: I
authors.lastname: Mercado-Uribe
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: Tao
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pathak
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Multani
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kuang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Bast
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu