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Functional Analysis of Distinct and Co-existing Transcriptional Programs Regulating Tumor Dormancy

Award Number: R01CA266443
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Functional Analysis of Distinct and Co-existing Transcriptional Programs Regulating Tumor Dormancy - Presence of disseminated tumor cells (DTCs) following successful treatment of primary tumors poses a risk factor for metastasis which is the leading cause of cancer mortality. However, current knowledge on mechanisms controlling the state of DTCs (persistent dormancy vs. reactivation) is limited. Only detailed knowledge of DTC biology will open therapeutic alternatives which will extend remission. We demonstrated that the transcription factor NR2F1/COUP-TFI triggers the dormancy phase of DTCs in head and neck squamous cell carcinoma (HNSCC) by regulating the retinoic acid pathway and inducing a long-lasting cell cycle arrest. Here we present new preliminary data showing that the dormant HNSCC DTC population is heterogeneous and that the pluripotency gene SOX2 is upregulated in a subpopulation of DTCs that co-exist with, but are distinct from, NR2F1+ dormant DTCs in the lungs and lymph nodes. SOX2 maintains the dormancy of DTCs by upregulating LIF (leukemia inhibitory factor) and OSM (oncostatin M) signaling and by repressing retinoic acid- and MYC-related genes. In addition, the SOX2-driven dormancy program involves chromatin remodeling and appears to dictate a much shorter dormancy phase that facilitates higher metastasis initiating capacity (reactivation). We hypothesize that SOX2-induced dormancy is enabled via enhancer regulation and LIF/OSM signaling which facilitates greater reactivation potential and metastasis-initiating capacity than the less reactivation prone NR2F1+ DTCs. We also propose that a persistent state of dormancy with lower reactivation potential can be induced in SOX2+ DTCs by inducing NR2F1 activity. Lastly, we propose that SOX2+ DTCs can be selectively targeted by chemotherapy due to their higher reactivation rate. The specific aims of this study are: SA1. To identify the mechanism of dormancy and the reactivation rate controlled by SOX2 in DTCs. We will identify and functionalize the transcriptional targets of SOX2 (including LIF/OSM) in controlling the dormancy and rate of reactivation by using ChIP-Seq analysis, gain and loss of function, lung-explant organ culture model, and validation in human biospecimens. SA2. To determine whether SOX2+ dormant DTCs can be targeted to inhibit their reactivation or eliminated. We will determine 1- whether SOX2-driven dormancy program can be converted into an NR2F1- driven program with low reactivation potential by using protocols to induce NR2F1 activity and 2- whether SOX2+ DTCs can be selectively targeted by chemotherapy due to their higher reactivation rate, compared to NR2F1+ DTCs by using cellular barcoding and clonal tracking technology. Our long-term objective is to identify predictive biomarkers of the DTC status (dormant vs proliferating) and to gain insight necessary for therapeutic strategies to either maintain DTCs in a stable dormancy phase or induce their eradication.


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 = $384,300 )
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	4	4/21/2026	NON-COMPETING CONTINUATION	$384,300
														Subtotal = $384,300

Issue Date FY: 2025 ( Subtotal = $384,300 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	3	6/2/2025	NON-COMPETING CONTINUATION	$38,430
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	3	4/7/2025	NON-COMPETING CONTINUATION	$345,870
														Subtotal = $384,300

Issue Date FY: 2024 ( Subtotal = $385,985 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	2	8/22/2024	NON-COMPETING CONTINUATION	$20,900
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	2	4/18/2024	NON-COMPETING CONTINUATION	$365,085
														Subtotal = $385,985

Issue Date FY: 2023 ( Subtotal = $384,300 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	1	4/21/2023	NEW	$384,300
														Subtotal = $384,300

Grand Total All Awards = $1,538,885

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Functional Analysis of Distinct and Co-existing Transcriptional Programs Regulating Tumor Dormancy

Award Number: R01CA266443

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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