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Dynamic Interactions of the Ovarian-Fallopian Axis in High Grade Serous Ovarian Cancer

Award Number: R01CA240301
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Dynamic Interactions of the Ovarian-Fallopian Axis in High Grade Serous Ovarian Cancer - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $588,667 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	8	7/17/2026	NON-COMPETING CONTINUATION	$588,667
														Subtotal = $588,667

Issue Date FY: 2025 ( Subtotal = $592,455 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	001	7	6/25/2025	NON-COMPETING CONTINUATION	$592,455
2025	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	5	2/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $592,455

Issue Date FY: 2024 ( Subtotal = $622,570 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	002	6	7/26/2024	COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	6	7/10/2024	COMPETING CONTINUATION	$621,782
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	001	6	7/18/2024	COMPETING CONTINUATION	$788
														Subtotal = $622,570

Issue Date FY: 2023 ( Subtotal = $527,572 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	5	6/21/2023	NON-COMPETING CONTINUATION	$527,572
														Subtotal = $527,572

Issue Date FY: 2022 ( Subtotal = $528,019 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	4	7/18/2022	NON-COMPETING CONTINUATION	$528,019
														Subtotal = $528,019

Issue Date FY: 2021 ( Subtotal = $538,813 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	3	6/9/2021	NON-COMPETING CONTINUATION	$538,813
														Subtotal = $538,813

Issue Date FY: 2020 ( Subtotal = $610,860 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	001	2	9/3/2020	SUPPLEMENT FOR EXPANSION	$71,919
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	002	2	9/10/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	2	6/12/2020	NON-COMPETING CONTINUATION	$538,941
														Subtotal = $610,860

Issue Date FY: 2019 ( Subtotal = $551,809 )
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	1	7/1/2019	NEW	$551,809
														Subtotal = $551,809

Grand Total All Awards = $4,560,765

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Dynamic Interactions of the Ovarian-Fallopian Axis in High Grade Serous Ovarian Cancer

Award Number: R01CA240301

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/10/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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