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SPATIALLY MAPPING OF POOLED IN VIVO CRISPR SCREENS IN THE TUMOR MICROENVIRONMENT

Award Number: DP2CA281605
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/26/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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SPATIALLY MAPPING OF POOLED IN VIVO CRISPR SCREENS IN THE TUMOR MICROENVIRONMENT - RFA-RM-21-016: New Innovator Award– Project Summary. Jellert T. Gaublomme PROJECT SUMMARY To understand how cellular behavior informs pathogenesis we need to study cells in their native tissue environment. Only by doing so can we elucidate the influence of signals received through cell-to-cell interactions and microenvironmental factors. For example, tumors evade immune mediated clearing by silencing T-cells, which receive signals from cancer cells, stromal cells, macrophages, and the extracellular matrix, to name a few. These numerous tissue microenvironmental influences are not captured by in vitro studies most often used during pharmaceutical screens for therapeutic targets. To extensively chart the cellular architecture of the tumor microenvironment, and the intercellular signaling that leads to an immunosuppressive environment, I will develop and apply an approach that profiles the transcriptomic and proteomic state of cells in situ. Once the tumor microenvironment is mapped, it is crucial to identify signaling genes that drive immunosuppression. Targeting immunomodulatory signaling can yield therapeutic breakthroughs, as evidenced by recent advances in immune checkpoint inhibition. Recently developed in vivo pooled CRISPR screens are a powerful high-throughput modality to identify genetic regulators. However, to date, these assays require cells to be isolated from their native tissue context prior to analysis. Our proposal is to pioneer a screening method that enables optical in situ identification of the CRISPR perturbation at the single-cell level in the native tissue context, enabling us to study the corresponding changes in tissue architecture and cell-to-cell interactions. Our approach is poised to elucidate mechanistic insights, and selection of the most promising therapeutic targets. A therapeutic treatment is in essence a perturbation on a tumor that developed unperturbed. In current in vivo screens however, tumors arise from cells that are perturbed for the screening genes, thus compromising normal tumorigenesis and development of a native tumor microenvironment. Another key innovation of our proposal is to decouple tumor induction and the time at which we perturb the signaling genes we are screening for. To achieve temporal decoupling, we induce the CRISPR perturbation at a desired stage of tumor development. Our inventive strategy allows for an uninhibited tumorigenesis process, allowing normal vasculature, extracellular matrix and immune interaction development, similar to the tumor development process in patients. In a first deployment of our innovative framework we aim to prioritize therapeutically targetable genes driving a model of hepatocellular carcinoma (HCC), a deadly cancer with poor 5-year survival in patients, where currently only a small subset of patients benefits from immune checkpoint therapy. Recent studies demonstrate that combination therapies in HCC can be more effective than single agents. Testing all pairwise combinations of promising targets is prohibitively costly and experimentally intractable. Leveraging our proposed methodology, we will identify promising combinations of therapeutic targets by performing higher order genetic CRISPR screening in vivo. 1


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 = $0 )
2026	2022	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	1	1/9/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $972,262 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	2	8/27/2025	EXTENSION WITH OR WITHOUT FUNDS	$972,262
														Subtotal = $972,262

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	1	9/12/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $1,480,500 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	1	9/26/2022	NEW	$1,480,500
														Subtotal = $1,480,500

Grand Total All Awards = $2,452,762

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SPATIALLY MAPPING OF POOLED IN VIVO CRISPR SCREENS IN THE TUMOR MICROENVIRONMENT

Award Number: DP2CA281605

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/26/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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