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Cholesterol metabolism in mesenchymal colorectal cancer

Award Number: R01CA275846
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/09/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Cholesterol metabolism in mesenchymal colorectal cancer - PROJECT SUMMARY The overarching goal of this proposal is to identify novel addictions in mesenchymal colorectal cancer (CRC) that will create new vulnerabilities to be targeted therapeutically. This type of aggressive CRC shows a microsatellite stable phenotype, characterized by a strong reactive desmoplastic stroma and immunosuppressed microenvironment. Mesenchymal CRC is enriched in a transcriptomic CMS4 signature, affects about 30-40% of all CRCs with the poorest prognosis, and lacks effective therapies. Our recently published and preliminary data demonstrated that the loss of the two atypical protein kinase Cs (aPKCs; PKCλ/iota and PKCzeta, encoded by PRKCI and PRKCZ genes) drives the mesenchymal phenotype in mouse intestinal tumors. Furthermore, interrogation of human specimens and transcriptional datasets of CRC patients established the aPKCs as new suppressors of mesenchymal CRC. Our data also show that PKCλ/iota is the one whose inactivation unleashes transformation through the mesenchymal route, and new preliminary results, which constitute the foundation of this proposal, demonstrated that aPKC inactivation in several models results in the upregulation of a cholesterol biosynthetic signature and promotes cholesterol synthesis in vivo as evidenced by metabolic tracing experiments in mice. Analysis of human CRC data and samples demonstrate a positive correlation between the activation of the cholesterol biosynthetic pathway and mesenchymal CRC, associated with a negative correlation with aPKC levels. Also, PKCλ/iota directly phosphorylates SCAP, an obligate regulator of SREBP2 processing, which is the master regulator of cholesterol biosynthesis. Therefore, the central hypothesis of this application is that PKCλ/iota by phosphorylating SCAP restrains the cholesterol biosynthetic pathway to repress tumorigenesis in mesenchymal CRC. Building on our strong preliminary data, we will (Aim 1) determine the role of increased cholesterol metabolism in mesenchymal CRC initiation and progression. To that end, we will determine the impact of feeding a high-cholesterol diet (Aim 1.1) or blocking cholesterol metabolism in vivo (Aim 1.2) in tumor initiation and progression of mesenchymal CRC tumors driven by PKCλ/iota deficiency; and determine the human relevance of PKCλ/iota-regulated cholesterol metabolism in mesenchymal CRC (Aim 1.3). We will also (Aim 2) determine the molecular mechanisms whereby PKCλ/iota regulates cholesterol biosynthesis in mesenchymal CRC tumorigenesis. Therefore, we will (Aim 2.1) determine the impact of PKCλ/iota-mediated SCAP phosphorylation on regulating the SCAP/SREBP2 complex at a mechanistic level; and (Aim 2.2) determine the functional contribution of PKCλ/iota-mediated SCAP phosphorylation to CRC in vivo. The results from this proposal will allow the identification of new targets as therapeutic points for intervention in mesenchymal CRC.


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: 2025 ( Subtotal = $523,143 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	000	3	11/19/2024	NON-COMPETING CONTINUATION	$470,829
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	001	3	6/2/2025	NON-COMPETING CONTINUATION	$52,314
														Subtotal = $523,143

Issue Date FY: 2024 ( Subtotal = $496,987 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	001	2	4/15/2024	NON-COMPETING CONTINUATION	$26,158
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	2	11/14/2023	NON-COMPETING CONTINUATION	$470,829
														Subtotal = $496,987

Issue Date FY: 2023 ( Subtotal = $523,143 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	1	12/9/2022	NEW	$523,143
														Subtotal = $523,143

Grand Total All Awards = $1,543,273

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Cholesterol metabolism in mesenchymal colorectal cancer

Award Number: R01CA275846

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/09/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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