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Role of LRG1 in colorectal cancer tumorigenesis

Award Number: R37CA278982
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Role of LRG1 in colorectal cancer tumorigenesis - Patients with metastatic colorectal cancer (mCRC) have substantially worse outcomes than those with primary and localized CRC. Over 80% of CRC metastases occur in the liver, which has a unique endothelial cell (EC)- rich microenvironment. Distinct from precedent EC studies focused on angiogenesis and vascular remodeling, we discovered that liver ECs secrete soluble factors to promote mCRC development in a paracrine fashion. Specifically, we found that human epidermal growth factor receptor 3 (HER3, also known as Erbb3) is a key mediator of EC-induced mCRC growth in the liver. However, we found that liver ECs activate HER3 independent of the only known HER3 ligand, neuregulins. Here, we made the paradigm-shifting discovery that leucine rich alpha-2-glycoprotein 1 (LRG1) secreted from liver ECs is a novel HER3 ligand that activates CRC-associated HER3 and promote CRC cell growth. Moreover, systemic inhibition of LRG1 attenuates the growth of CRC subcutaneous (subQ) xenografts and increases mouse survival in an orthotopic mCRC model. The GOAL of this proposal is to determine the role of LRG1 as a novel HER3 ligand in promoting mCRC development, and to elucidate the mechanisms by which LRG1 binds and activates HER3. We HYPOTHESIZE that LRG1 is a novel HER3 ligand and that the LRG1-HER3 signaling axis plays a critical role in CRC liver metastases development. We will test this hypothesis in two SPECIFIC AIMS: Aim 1 will determine roles of EC-secreted LRG1 in promoting mCRC initiation and outgrowth in clinically relevant mCRC models with EC-specific LRG1 knockout mice, a LRG1 neutralizing antibody, and patient-derived xenografts and organoids. Aim 2 will elucidate the mechanisms by which LRG1 binds and activate HER3, and determined the correlations between HER3 activation and mCRC patient outcomes. INNOVATIONS of this project include determination of a novel role of LRG1 in promoting mCRC development, identification of LRG1 as a novel HER3 ligand, and elucidation of the mechanisms of LRG1 activating HER3. Successful completion of the proposed studies will also identify HER3 activation as a potential prognostic biomarker for patients with mCRC, and lay a foundation for developing new therapeutic strategies for targeting LRG1 and other amenable component(s) in the LRG1-HER3 signaling cascade.


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 = $331,459 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	3	1/21/2026	NON-COMPETING CONTINUATION	$331,459
														Subtotal = $331,459

Issue Date FY: 2025 ( Subtotal = $368,288 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	2	1/8/2025	NON-COMPETING CONTINUATION	$331,459
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	001	2	6/9/2025	NON-COMPETING CONTINUATION	$36,829
														Subtotal = $368,288

Issue Date FY: 2024 ( Subtotal = $368,288 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	1	2/1/2024	NEW	$368,288
														Subtotal = $368,288

Grand Total All Awards = $1,068,035

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Role of LRG1 in colorectal cancer tumorigenesis

Award Number: R37CA278982

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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