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Identification and characterization of cancer cell states by novel computational and experimental technologies - Resubmission - 1

Award Number: U01CA260432
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/21/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Identification and characterization of cancer cell states by novel computational and experimental technologies - Resubmission - 1 - SUMMARY Tumors are complex systems composed of genetically and transcriptionally heterogeneous cells, and this heterogeneity has been implicated as a cause of drug resistance and overall mortality. Understanding intra- tumor heterogeneity is therefore likely to have widespread impact, both fundamental and clinical. The advent of single-cell RNA-Seq has led to the detection of transcriptionally distinct states among cancer cells across a wide range of tumor types and stages. However, the field lacks robust computational and experimental technologies to functionally identify and characterize these cancer cell states. In this project, we take a gene module-centric view to define cell states in a rigorous and widely applicable manner. We will validate the importance of each cell state using human samples and the zebrafish melanoma model, which has exceptional capabilities for imaging and perturbation of cell states throughout tumor progression and metastasis. To systematically characterize these cell states experimentally, we propose methods to assay their interdependencies within the tumor and with elements of the microenvironment. Our genetically engineered zebrafish will mark each cancer cell state with a fluorescent reporter and an ablation cassette, providing a flexible experimental platform to study and perturb each cell state. The reporter will enable us to sort cancer cell states and study them individually, with a particular emphasis on their plasticity. By systematically disrupting cancer cell states, we will further elucidate their individual contributions to tumor initiation, progression and metastasis. Using a spatial transcriptomics approach and integrating with single-cell RNA-seq data, we will map cancer cell states in relation to their microenvironment to screen for putative interactions. Finally, we will directly test predicted interactions between specific cancer cell states and the immune compartment using T cell-deficient fish. Throughout our three Aims, we adopt a systems biology workflow that iteratively cycles through modes of observations, perturbations, and refinement of our model of the functional role of cancer cell states during tumor progression. Our proposal collectively integrates the complementary expertise of the White and Yanai labs and sets out to significantly improve our understanding of intratumoral heterogeneity through the lens of cancer cell states.


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 = $518,035 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	4	4/16/2025	NON-COMPETING CONTINUATION	$518,035
2025	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	3	12/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $518,035

Issue Date FY: 2024 ( Subtotal = $546,816 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	3	4/26/2024	NON-COMPETING CONTINUATION	$546,816
2024	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	2	11/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $546,816

Issue Date FY: 2023 ( Subtotal = $564,082 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	2	6/9/2023	NON-COMPETING CONTINUATION	$564,082
														Subtotal = $564,082

Issue Date FY: 2022 ( Subtotal = $592,969 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	1	6/21/2022	NEW	$592,969
														Subtotal = $592,969

Grand Total All Awards = $2,221,902

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Identification and characterization of cancer cell states by novel computational and experimental technologies - Resubmission - 1

Award Number: U01CA260432

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 06/21/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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