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Principal Investigator: Wu-Min Deng
Organization: TULANE UNIVERSITY OF LOUISIANA
Fiscal Year: 2024
Award: $341,248
Funding agency: National Cancer Institute
Project Summary
Ploidy variation is a cancer hallmark and is frequently associated with poor prognosis in high-grade cancers.
Such variation can include an increase in chromosome set (polyploidy), a difference of chromosomes in a
set (aneuploidy), or regional ploidy changes and copy number variations (CNVs). Genome-wide studies of
multiple cancer specimens have shown that whole genome doubling is one of the most common molecular
abnormalities in human cancers and is closely linked to other copy number alterations. However, how
exactly polyploidy contributes to tumor growth, progression and malignancy remains largely unclear. Using
a simple and highly reproducible Drosophila tumor model, where an active form of Notch (NICD) drives
tumorigenesis in an epithelial transition zone (TZ), our preliminary studies indicate that tumor progression is
driven by occurrences of polyploid mitosis, endoreplication, and ploidy reduction divisions. Both polyploid
mitosis and depolyploidization are error-prone and can lead to chromosome abnormalities such as CNVs
and polyaneuploidy, resulting in intratumoral heterogeneity in DNA ploidy. Comparative RNA-Seq analyses
revealed that DNA damage response (DDR) genes are upregulated in these NICD-TZ tumors. Genetic
epistasis studies have further shown that some of these DDR genes are required for the ploidy reduction
division. Additionally, these tumors show sexual dimorphism regarding tumor growth and progression.
Based on these findings, we hypothesize that polyploidy and associated cell-cycle variants are critical for
continued tumor growth and increased tumor-cell genome instability during tumor progression. To test this
hypothesis, we will carry out studies proposed in the following two aims: (1) to determine how polyploid cell
divisions contribute to tumor growth and progression; (2) to characterize the sexual dimorphism of the
NICD-TZ tumor model. The successful execution of the proposed studies will lead to a better
understanding of intratumor ploidy heterogeneity and cancer evolution, as well as improved strategies in
cancer prevention and treatment in a sex-dependent manner.
Terms: <Aberrant Chromosome><Aneuploid><Aneuploidy><Apoptosis><Apoptosis Pathway><Cancer Treatment><Cancers><Cell Body><Cell Cycle><Cell Death><Cell Division Cycle><Cell division><Cells><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosomal Instability><Chromosomal, Gene, or Protein Abnormality><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome Instability><Chromosome abnormality><Chromosomes><Copy Number Polymorphism><Cytogenetic Aberrations><Cytogenetic Abnormalities><Cytogenetic or Molecular Genetic Abnormality><DNA Content><DNA Damage><DNA Index><DNA Injury><DNA Ploidy><Development><Differences between sexes><Differs between sexes><Drosophila><Drosophila genus><Drug resistance><Early Diagnosis><Early treatment><Environmental Factor><Environmental Risk Factor><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epistasis><Epistatic Deviation><Epithelium><Evolution><Female><Generalized Growth><Genes><Genetic><Genetic Abnormality><Genetic Diversity><Genetic Epistasis><Genetic Variation><Genome Instability><Genomic Instability><Growth><Heterogeneity><Human><Interaction Deviation><Intratumoral heterogeneity><Link><M Phase><Maintenance><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mitosis><Mitosis Stage><Modeling><Modern Man><Molecular Abnormality><Oncogenesis><Pattern><Play><Ploidies><Polyploid><Polyploid Cells><Polyploidy><Prognosis><Programmed Cell Death><RNA Seq><RNA sequencing><RNAseq><Reproducibility><Research><Research Specimen><Role><Sex Differences><Sexual differences><Specimen><Testing><Tissue Growth><Tumor Cell><Variant><Variation><anti-cancer therapy><cancer cell><cancer prevention><cancer progenitor><cancer progenitor cells><cancer progression><cancer stem cell><cancer therapy><cancer-directed therapy><chromosomal defect><chromosome complement><chromosome defect><comparative><copy number variant><copy number variation><developmental><dimorphism><drug resistant><early detection><early therapy><entire genome><environmental risk><epigenetically><epistatic relationship><fruit fly><full genome><gene x gene interaction><genetic epistases><genome wide analysis><genome wide studies><genome-wide analysis><genome-wide identification><heterogeneity in tumors><improved><in vivo><intra-tumoral heterogeneity><intratumor heterogeneity><male><malignancy><malignant progenitor><malignant stem cell><molecular aberrations><necrocytosis><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><notch><notch protein><notch receptors><novel><ontogeny><programs><repair><repaired><resistance to Drug><resistant to Drug><response><sex><sex based differences><sex dimorphism><sex-dependent differences><sex-related differences><sex-specific differences><sexual dimorphism><sexually dimorphic><social role><tool><transcriptome sequencing><transcriptomic sequencing><tumor><tumor growth><tumor heterogeneity><tumor progression><tumorigenesis><whole genome>