R01CA287524

Polypoidy and sex dimorphism in a Drosophila tumor model - 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 (polypoidy), 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 polypoidy 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 polypoid mitosis, endoreplication, and ploidy reduction divisions.

Both polypoid mitosis and depolypoidization 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 polypoidy 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 polypoid 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.

The Administrators Of Tulane Educational Fund

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

New Orleans, Louisiana 701122632 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 99% from $341,248 to $677,516.