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Principal Investigator: Joanna E Burdette
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $622,570
Funding agency: National Cancer Institute
Ovarian cancer is the most lethal cancer of the female reproductive system, with over 21,000 new ovarian
cancer diagnoses and 14,000 deaths annually in the US. The total lifetime number of ovulations is a key risk
factor for developing ovarian cancer. Factors that repress ovulation reduce the risk of ovarian cancer, such as
oral contraceptives, pregnancy, lactation, and late menarche. The most common and deadly histotype of ovarian
cancer, termed high grade serous cancer (HGSC), likely originates from the fallopian tube epithelial cells, and
not the ovary. The frequent detection of tumors in the ovary, which resulted in the name “ovarian cancer”,
suggests that the ovary provides a unique anatomical location for tumor migration and expansion. Since most
research supports that the fallopian tube epithelium (FTE) is the source of ovarian cancer, it becomes critical to
understand how ovulation contributes to tumor initiation in this site. Our team developed three-dimensional
organotypic cultures supported in a state-of-the-art microfluidic platform that supports the ovary to produce
dynamic hormone profiles that closely mimic the 28-day human reproductive menstrual cycle and ovulation on
platform. This R01 renewal builds on this successful collaboration to expand our technology and models to
elucidate the mechanisms whereby blocking ovulation prevents FTE carcinogenesis and ovarian colonization.
We hypothesize that ovulation and the ovarian microenvironment contributes to the development FTE-derived
high grade serous tumors and that ovarian secreted factors drive primary metastasis. Aim 1 leverages our ability
to ovulate multiple ovaries in our MPS system called PREDICT-MOS to investigate mechanisms of
transformation. Using a unique panel of isogenic cell lines that include non-tumorigenic cells, preneoplastic lesion
models, and tumor models all derived from fallopian tube origin we will investigate how secreted factors from the
ovary produced during ovulation impact proliferation, soft agar colony formation, and spheroids. We will
determine if ovarian secretions increase DNA damage, replication stress, and copy number variation. Lastly, we
test if exposure to ovulation drives tumor formation. Aim 2 will focus on the notion that ovulation generates a
preneoplastic lesion and increased stemness through a secretory cell outgrowth using innovative iPSC-derived
fallopian tube organoids. Organoids will be engineered to model early tumor lesions and monitored in terms of
transformation in response to ovulation on platform. In Aim 3, we will investigate the mechanisms responsible
for fallopian tube tumor cell colonization of the ovary. Proteomics of ovulatory secretions found both versican
and IGF2 are higher after ovulation. We will investigate prevention of ovarian colonization by blocking versican
and IGF2 signaling in cell lines, 3D bioprinted models, primary tissue, and in vivo. Overall, this grant will employ
unique devices, primary human tissues, and three dimensional preneoplastic and tumor models to unveil new
biological targets to reduce tumor initiation and spread of fallopian derived high grade serous cancer in the
ovarian microenvironment.
Terms: <3-D><3-D print><3-D printer><3-Dimensional><3D><3D Print><3D cell culture><3D culture><3D printer><3D printing><53BP1><Adhesions><Agar><Age><Anatomic Sites><Anatomic structures><Anatomy><Biologic Models><Biological><Biological Models><Body System><Body Tissues><Breast Feeding><Breast fed><Breastfed><Breastfeeding><CD44><CD44 gene><Cancer Cause><Cancer Etiology><Cancer Induction><Cancers><Carcinoma><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Cessation of life><Clinical><Collaborations><Copy Number Polymorphism><DNA Damage><DNA Injury><Data><Death><Detection><Development><Devices><Disease><Disorder><Endocrine Gland Secretion><Engineering><Epithelial Cells><Epithelial cancer><Epithelium><Exposure to><Fallopian Tube Cancer><Fallopian Tube Neoplasms><Fallopian Tube Tumor><Fallopian Tubes><Female Genital System><Female Reproductive Cancer><Gestation><Grant><Gynecologic Cancer><Gynecological Cancer><HG38><Heterograft><Heterologous Transplantation><Hormones><Human><IGF2><IGF2 gene><Intracellular Communication and Signaling><Invaded><LGR5><LGR5 gene><Lactation><Lesion><Location><MDU3><MMAC1><MMAC1 protein><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Female Reproductive System Neoplasm><Malignant Gynecologic Neoplasm><Malignant Gynecologic Tumor><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Female Reproductive System><Malignant Tumor of the Ovary><Malignant fallopian tube tumor><Malignant neoplasm of fallopian tube><Malignant neoplasm of ovary><Mammalian Oviducts><Measures><Menarche><Menstrual cycle><Metastasis><Metastasis to Ovary><Metastasize><Metastatic Lesion><Metastatic Malignant Neoplasm to the Ovary><Metastatic Malignant Tumor to the Ovary><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Microfluidics><Model System><Modeling><Modern Man><Monitor><Murine><Mus><Mutated in Multiple Advanced Cancers 1><Names><Neoplasm Metastasis><Oral Contraceptives><Organ System><Organoids><Ovarian><Ovarian Metastasis><Ovary><Ovary Cancer><Ovulation><PHTS gene><PHTS protein><PTEN><PTEN gene><PTEN protein><PTEN1><Paper><Pathway interactions><Penetration><Pgp1><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Predictive Factor><Pregnancy><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Process><Proliferating><Protein Secretion><Proteins><Proteomics><Publishing><Repression><Research Support><Risk Factors><Risk Reduction><Role><Salpinx><Secondary Neoplasm><Secondary Tumor><Secretory Cell><Serous><Signal Transduction><Signal Transduction Systems><Signaling><Site><Source><Stem Cell like><Strains Cell Lines><Stromal Cells><Structure><Surface><Survival Rate><System><TP53BP1><Technology><Testing><Therapeutic Hormone><Time><Tissues><Tumor Cell><Tumor Cell Migration><Tumor Suppressor Proteins><Uterine Tubes><WNT4><WNT4 gene><Wingless-Type MMTV Integration Site Family, Member 4><Women's mortality><Xenograft><Xenograft procedure><Xenotransplantation><ages><bio-printing><biologic><biological signal transduction><bioprinting><birth control pill><blocking factor><cancer diagnosis><cancer metastasis><cancer progenitor><cancer progenitor cells><cancer stem cell><carcinogenesis><copy number variant><copy number variation><corpus luteum><cultured cell line><death among females><death among women><death in females><death in women><death rate among women><death rate in women><developmental><epithelial carcinoma><female death><female genital tract><female mortality><female reproductive body system><female reproductive organ system><female reproductive system><female reproductive tract><fimbria><gynecologic body system><gynecologic malignancy><gynecologic organ system><gynecological malignancy><high risk><human tissue><iPS><iPSC><iPSCs><improved><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><inhibitor><innovate><innovation><innovative><lactating><lactational><malignancy><malignant progenitor><malignant stem cell><migration><mortality among females><mortality among women><mortality in females><mortality in women><mutated in multiple advanced cancers 1 protein><name><named><naming><neoplasm/cancer><neoplastic><neoplastic cell><novel><organ on a chip><organ on chip><ovarian cancer><oviduct><p202><p53-binding protein 1><p53BP1><pathway><phosphatase and tensin homologue on chromosome ten><prevent><preventing><progenitor cell markers><progenitor cell niche><progenitor cell population><progenitor markers><progenitor niche><progenitor population><progenitor stem cell markers><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><replication stress><reproductive><response><risk-reducing><small molecule><social role><spheroids><stem and progenitor cell niche><stem and progenitor cell population><stem cell biomarkers><stem cell characteristics><stem cell markers><stem cell niche><stem cell population><stemness><three dimensional><three dimensional cell culture><three dimensional printing><transcriptomics><treatment strategy><tumor><tumor cell metastasis><tumor initiation><tumor suppressor><tumorigenic><versican><women's death><women's death rate><women's genital tract><women's reproductive tract><xeno-transplant><xeno-transplantation><µfluidic>