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Pleiotropic functions of FOXC2 in EMT, stem cells and breast cancer progression

Award Number: R01CA155243
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/16/2011
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Pleiotropic functions of FOXC2 in EMT, stem cells and breast cancer progression - Development of resistance to therapies, tumor relapse, and metastasis pose significant risks to breast cancer patients and are responsible for the majority deaths among these cancer patients. Recent studies have demonstrated that the developmental process is known as epithelial-mesenchymal-transition (EMT) as well as a subpopulation of cancer cells termed cancer stem cells (CSC), in these various processes. We and others have shown that the EMT program and stem cell properties are interconnected, and specifically, cancer cells are capable of acquiring stem cell attributes through the activation of EMT. This suggested that targeting EMT program may reduce the disease burden and will decrease death among cancer patients. However, the dearth of signaling pathways emanating from the tumor microenvironment capable of inducing EMT - including inflammatory cytokines and transforming growth factor β-1 (TGFβ1) makes it impossible to therapeutically target EMT. Cumulative studies from our laboratory over the last 9 years have resulted in the seminal identification of the transcription factor FOXC2, as a key player in metastasis and also as a common downstream effector of multiple EMT-signaling pathways and indispensable for the procurement of CSC properties. A characteristic feature of CSCs is their capability to self-renew via asymmetrical or symmetrical self-renewal type of cell divisions thereby enabling the continued existence and expansion of the CSC pool. The current proposal will systematically test the role of FOXC2 as a critical element of the molecular switch facilitating CSC self-renewal and expansion, and investigate if aberrant activation of FOXC2 leads to increase in CSC populations via Notch signaling, resulting in tumor progression and metastasis. We will use a combination of in vitro-, and in vivo tumor models, and patient-derived xenografts as well as genetically engineered mouse models to tease out this process. We will also examine the function of TGFβ1, a physiologically relevant inducer of EMT, in dictating FOXC2-induced CSC expansion. Also, we will evaluate FOXC2-regulated mitotic bookmarking in maintaining the identity of the CSCs following stem cell division. Finally, we will test select small molecule inhibitors capable of modulating FOXC2-function in selectively preventing CSC expansion during EMT. Significance: In summary, our proposal will not only help clarify the fundamental processes regulating CSC self-renewal and expansion of CSCs during EMT but will also contribute to designing novel strategies that would provide an opportunity to shift the balance of CSC towards more differentiated cells and exhaust therapy-resistant, metastasis-prone CSCs.


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 = -$4,799 )
2025	2022	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	10	1/14/2025	NON-COMPETING CONTINUATION	$0
2025	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Cancer Biology Research	001	11	8/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$4,799
														Subtotal = -$4,799

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Cancer Biology Research	000	11	8/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Cancer Biology Research	002	11	9/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Cancer Biology Research	001	11	7/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$321,099
2023	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	10	7/26/2023	NON-COMPETING CONTINUATION	-$321,099
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $322,106 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	10	7/11/2022	NON-COMPETING CONTINUATION	$322,106
2022	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	9	10/14/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $322,106

Issue Date FY: 2021 ( Subtotal = $328,680 )
2021	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	9	8/30/2021	NON-COMPETING CONTINUATION	$328,680
														Subtotal = $328,680

Issue Date FY: 2020 ( Subtotal = $328,680 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	8	8/3/2020	NON-COMPETING CONTINUATION	$328,680
														Subtotal = $328,680

Issue Date FY: 2019 ( Subtotal = $318,819 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	7	8/2/2019	NON-COMPETING CONTINUATION	$318,819
														Subtotal = $318,819

Issue Date FY: 2018 ( Subtotal = $328,680 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	6	7/20/2018	COMPETING CONTINUATION	$328,680
2018	2015	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	6/6/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $328,680

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	6/5/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $327,462 )
2015	2015	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	2/13/2015	NON-COMPETING CONTINUATION	$327,462
														Subtotal = $327,462

Issue Date FY: 2014 ( Subtotal = $317,638 )
2014	2014	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	5/9/2014	NON-COMPETING CONTINUATION	$22,922
2014	2014	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	3/13/2014	NON-COMPETING CONTINUATION	$294,716
														Subtotal = $317,638

Issue Date FY: 2013 ( Subtotal = $309,703 )
2013	2013	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	7/1/2013	NON-COMPETING CONTINUATION	$161,441
2013	2013	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	2/7/2013	NON-COMPETING CONTINUATION	$148,262
														Subtotal = $309,703

Issue Date FY: 2012 ( Subtotal = $333,707 )
2012	2012	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	3/15/2012	NON-COMPETING CONTINUATION	$333,707
														Subtotal = $333,707

Issue Date FY: 2011 ( Subtotal = $333,707 )
2011	2011	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	3/16/2011	NEW	$333,707
														Subtotal = $333,707

Grand Total All Awards = $3,244,383

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Pleiotropic functions of FOXC2 in EMT, stem cells and breast cancer progression

Award Number: R01CA155243

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/16/2011

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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