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Enabling in vivo barcoded single-cell multiomics-compatible genome-wide screens in personalized tumor models using defined-copy somatic transgenesis

Award Number: R33CA278564
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/08/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Enabling in vivo barcoded single-cell multiomics-compatible genome-wide screens in personalized tumor models using defined-copy somatic transgenesis - PROJECT SUMMARY / ABSTRACT CRISPR technology have massively expanded our ability to interrogate the genetic mechanisms of cancer and define therapeutic avenues. Techniques have evolved over the past five years for the generation of massive scale CRISPR genetic screens linked to single cell transcriptomics. However, the ability to perform such screen in vivo in genetically engineered models remains cumbersome. Over the past several years, we have pioneered an electroporation-based somatic mutation method for rapid, non-invasive, somatic transgenesis for high throughput validation of tumor driver genes using mosaic analysis with dual recombinase-mediated cassette exchange (MADR). The central theme of this grant application is to generate, optimize, and validate MADR Perturb-seq—a novel suite of genetic tools that facilitate massive scale genetic screens in the context of both in vivo murine somatic transgenesis as well as inducible editing in human iPSC-derived organoids. We will exploit our experience with electroporation based modeling to rapidly optimize and empirically test MADR Perturb-seq. The overall objective of the proposal is to perform advanced development of this combined MADR-CRISPR approach to allow for generalized use in diverse tumor contexts and, therefore, demonstrate the potential of this technology to transform cancer research. We propose to carry out this work in three parts. The focus of Specific Aim 1 is to Optimize CRISPR elements, ORFs, and molecular barcodes for use with somatic transgenic patient-derived tumor signatures and validate genetic tools for enabling multiplex genetic screens in an off the shelf CRISPR/Cas9 mouse. The main goal of Specific Aim 2 is to validate MADR multiplexing screening in vivo at scale . Finally, in Aim 3, we will engineer approaches for highly multiplexed genetic screens using MADR combined with inducible elements and/or virally-delivered MADR elements in human engineered iPSCs. Successful completion of these experiments will yield unprecedented capabilities for genetically screening tumor mechanisms and potential therapeutic weaknesses.


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 = $410,332 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	002	2	6/16/2025	NON-COMPETING CONTINUATION	$41,032
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	2	1/14/2025	NON-COMPETING CONTINUATION	$369,300
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	001	2	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $410,332

Issue Date FY: 2024 ( Subtotal = $414,491 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	1	2/8/2024	NEW	$414,491
														Subtotal = $414,491

Grand Total All Awards = $824,823

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Enabling in vivo barcoded single-cell multiomics-compatible genome-wide screens in personalized tumor models using defined-copy somatic transgenesis

Award Number: R33CA278564

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/08/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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