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Post-translational SOX2 modification - a regulatory switch between self-renewal and differentiation in squamous cell carcinoma

Award Number: R01CA248175
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY SOX2 is a cell fate–determining transcription factor that is expressed in ~70% of cutaneous and head and neck squamous cell carcinomas (SCCs) in patients. SOX2 is highly enriched in stem cell–like tumor-propagating cells (TPCs), which are located within the basal SCC layer where they can self-renew or differentiate into suprabasal SCC cells without proliferative potential. Although we know SOX2 controls the fate choice between TPC self- renewal and squamous differentiation, it is unclear how its activity is regulated in SCCs and whether these regulatory mechanisms could be developed into therapies for cancer patients. Here, we propose to test the hypothesis that phosphorylation of SOX2 inhibits its activity, perturbs the SCC-specific SOX2-PITX1- TP63 self-renewal circuit that drives clonal expansion and SCC growth, and thereby restores the KLF4- dependent squamous differentiation program in SCCs. Our hypothesis is based on our preliminary studies, which showed that SOX2 can be phosphorylated and that this phosphorylation attenuates its activity in SCC cells. We propose to 1) test if SOX2 phosphorylation inhibits TPC self-renewal, clonal expansion, and SCC growth; 2) identify the kinases and phosphatases that regulate SOX2 phosphorylation and function; and 3) define the molecular mechanisms by which SOX2 activity governs TPC self-renewal, SCC growth, and differentiation in mouse and patient-derived SCC models. We expect our proposed research will explain the fate choice between TPC self-renewal and terminal differentiation on a molecular level and therefore provide new concepts for the rational development of pharmacological approaches that enforce the commitment of TPCs to terminally differentiate into SCC cells without proliferative potential.


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: 2024 ( Subtotal = $437,810 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	4	11/15/2023	NON-COMPETING CONTINUATION	$414,767
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	4	4/15/2024	NON-COMPETING CONTINUATION	$23,043
														Subtotal = $437,810

Issue Date FY: 2023 ( Subtotal = $454,783 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	3	11/21/2022	NON-COMPETING CONTINUATION	$417,658
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	3	3/14/2023	NON-COMPETING CONTINUATION	$37,125
														Subtotal = $454,783

Issue Date FY: 2022 ( Subtotal = $441,695 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	2	11/30/2021	NON-COMPETING CONTINUATION	$405,638
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	2	5/27/2022	NON-COMPETING CONTINUATION	$36,057
														Subtotal = $441,695

Issue Date FY: 2021 ( Subtotal = $453,875 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	1	11/27/2020	NEW	$453,875
														Subtotal = $453,875

Grand Total All Awards = $1,788,163

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Post-translational SOX2 modification - a regulatory switch between self-renewal and differentiation in squamous cell carcinoma

Award Number: R01CA248175

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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