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Characterization of ILEI/LIFR Axis-induced Intracellular Signaling

Award Number: F31CA257145
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 11/22/2023

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Characterization of ILEI/LIFR Axis-induced Intracellular Signaling - Project Summary Our lab has previously identified a mechanism of transforming growth factor beta (TGFβ)-mediated epithelial-to-mesenchymal transition (EMT) in murine mammary epithelium. We have shown that expression of the interleukin-like EMT inducer (ILEI) protein is necessary to induce EMT in murine mammary gland cells following exposure to TGFβ. ILEI has also been shown to increase the self-renewal capacity of epithelial cells following EMT, through its interaction with leukemia inhibitory factor receptor (LIFR), suggesting that the ILEI/LIFR signaling axis promotes breast cancer stem-cell (BCSC) phenotype. Further, our lab has shown that TGFβ-induced upregulation of LIFR is ILEI-dependent. In cells derived from a mouse tumor progression model created by our lab, spheroid formation capacity in non-adherent cell culture conditions is attenuated following either ILEI or LIFR knockdown. Additionally, orthotopic grafts of cells with ILEI or LIFR knockdown display a decrease in tumor growth and metastasis relative to control cells. We hypothesize that TGFβ-induced LIFR regulation contributes to metastases. The precise mechanisms of ILEI-mediated EMT and BCSC induction are unknown. Herein we aim to interrogate ILEI/LIFR axis-mediated mechanisms downstream of TGFβ exposure that influence (1) the regulation of LIFR protein expression and (2) the ensuing maintenance of self-renewal capacity and disease progression in our model. In Specific Aim 1, the LIFR promoter sequence will be examined to identify key factors regulating LIFR expression. In Specific Aim 2, transcriptomic data will be examined following ILEI/LIFR knockout to identify a signature of ILEI/LIFR-regulated gene expression and its association with self-renewal capacity. In Specific Aim 3, the role of LIFR will be examined in vivo to determine the impact of its expression upon outgrowth of pulmonary tumors following tail vein injection of cells into immunodeficient mice. Data from our experiments will characterize a signaling pathway associated with BCSC maintenance and will potentially identify novel therapeutic targets. Our findings may translate to novel treatments for dormancy and relapse in human metastatic breast cancer.


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: 2024 ( Subtotal = -$9,170 )
2024	2023	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Research Manpower	001	3	9/23/2024	NON-COMPETING CONTINUATION	-$4,043
2024	2023	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Research Manpower	000	3	3/7/2024	NON-COMPETING CONTINUATION	-$5,127
														Subtotal = -$9,170

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Research Manpower	001	3	6/6/2023	NON-COMPETING CONTINUATION	$942
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Research Manpower	000	3	2/1/2023	NON-COMPETING CONTINUATION	$46,752
														Subtotal = $47,694

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Research Manpower	001	2	5/20/2022	NON-COMPETING CONTINUATION	$716
2022	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Research Manpower	000	2	1/6/2022	NON-COMPETING CONTINUATION	$46,036
														Subtotal = $46,752

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Research Manpower	000	1	1/12/2021	NEW	$45,520
2021	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Research Manpower	002	1	2/5/2021	NEW	$516
2021	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Research Manpower	001	1	1/12/2021	NEW	$0
														Subtotal = $46,036

Grand Total All Awards = $131,312

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Characterization of ILEI/LIFR Axis-induced Intracellular Signaling

Award Number: F31CA257145

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 11/22/2023

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