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Dissecting hybrid epithelial-mesenchymal states in head and neck cancer

Award Number: R01DE032371
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Dissecting hybrid epithelial-mesenchymal states in head and neck cancer - PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer-related mortality, and most patients have poor outcomes, with a five-year survival rate that is less than 40%. The majority of deaths are attributable to metastasis and treatment failure, and unfortunately, our understanding of these pathways is incomplete. Consequently, there are no targeted therapies against these biologic processes. Recently, we performed a single cell analysis of HNSCC tumors that revealed a new transcriptional pathway – dubbed a hybrid epithelial/mesenchymal state (HEM) – as a critical driver of invasion and metastasis. This pathway is clearly distinct from the classical EMT pathway, as most key EMT transcription factors (TFs) were not expressed, with the exception of Snail2. The importance of this pathway to disease etiology was highlighted by the fact that the presence of the HEM signature in tumors was more predictive of treatment outcome than any other commonly used pathologic or demographic factor. The main driver of HEM appears to be the Snail2 transcription factor, but little is known about how Snail2 orchestrates HEM. We propose to determine the direct and indirect targets of Snail2 and assess their roles in promoting invasion and metastasis. This will reveal the proteins in the HEM pathway that promote tumor progression and thus represent targets for the rational design of therapeutics. Because HNSCC tumors are highly heterogeneous, we expect that bulk genomic approaches may not capture Snail2 targets that are activated or repressed in small subpopulations of tumor cells; yet such targets may still be highly relevant to the etiology of HNSCC progression. Therefore, we will also use a transposon-based technology known as “calling cards” that has single-cell resolution to make a comprehensive map of the transcriptional targets of Snail2 across distinct hybrid epithelial-mesenchymal cell states (Aim 1). Completion of this aim will identify the key functional targets of Snail2 and the knockdown, overexpression, and phenotyping assays that we propose will directly determine if the inhibition (or activation) of these targets blocks the effect of Snail2 on invasion and metastasis. To complement this approach, in Aim 2, we will investigate whether Snail2 acts cooperatively with other TFs and then learn the functional consequences of such cooperativity. This is important because while it has proven difficult to find small molecules that inhibit TF-DNA interactions, targeting cooperative interactions between TFs is emerging as a viable strategy for targeting oncogenic TFs. Furthermore, while these TFs cooperate with Snail2 at some loci, they likely activate other HEM genes independently or by interacting with one another, so identifying their targets will increase our knowledge of this pathway and expand the list of druggable HEM targets. Completion of these aims will provide a detailed map of a new pathway that plays a critical role in HNSCC metastasis and invasion and will identify opportunities for rational drug design and targeted therapeutics against HNSCC.


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 = $393,750 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Oral Diseases and Disorders Research	001	3	5/5/2025	NON-COMPETING CONTINUATION	$39,375
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Oral Diseases and Disorders Research	000	3	11/21/2024	NON-COMPETING CONTINUATION	$354,375
														Subtotal = $393,750

Issue Date FY: 2024 ( Subtotal = $383,834 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Oral Diseases and Disorders Research	001	2	6/13/2024	NON-COMPETING CONTINUATION	$31,334
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Oral Diseases and Disorders Research	000	2	11/14/2023	NON-COMPETING CONTINUATION	$352,500
														Subtotal = $383,834

Issue Date FY: 2023 ( Subtotal = $391,667 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Oral Diseases and Disorders Research	000	1	12/26/2022	NEW	$391,667
														Subtotal = $391,667

Grand Total All Awards = $1,169,251

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Dissecting hybrid epithelial-mesenchymal states in head and neck cancer

Award Number: R01DE032371

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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