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Roles of long-non-coding RNA, XIST, in brain metastasis of breast cancer

Award Number: R01CA205067
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Roles of long-non-coding RNA, XIST, in brain metastasis of breast cancer - During the late stage, 20-30% of patients with breast cancer develop brain metastasis and the one year survival rate of these patients is less than 20%. Therefore, it is of paramount importance to elucidate the molecular mechanism involved in the metastatic process in order to define a specific therapeutic target. Long non-coding RNAs (lncRNAs) that are distinguished from other small RNAs have recently drawn strong attention for their critical roles in tumor progression. We have examined the expression profile of lncRNAs in tumor tissues from primary and brain-metastatic lesions of breast cancer patients using our newly constructed lncRNA library. We found that (i) brain metastatic lesions express significantly lower amount of the lncRNA, XIST, which is linked to the X chromosome and plays a critical role in the X chromosome inactivation, (ii) when XIST was silenced in breast cancer cells, such cells significantly promoted brain metastatic growth in mice, and (iii) XIST expression presented a significant reverse correlation with brain but not with bone metastasis in patients. Therefore, we hypothesize that the loss of XIST promotes brain metastasis of breast cancer by stimulating EMT and self-renewal of tumor initiating cells through activation of the PLS3 and c-met pathways in the brain microenvironment. We also hypothesize that PTER suppresses metastatic ability of tumor initiating cells by blocking the c-Met pathway. To test these hypotheses, we will elucidate the molecular pathway through which loss of XIST stimulates the EMT by activating PLS3 on the X-chromosome (Aim 1). We will also decipher the mechanism by which the loss of XIST activates the c-Met pathway thereby promoting stemness of the metastasis initiating cells (Aim 2). Finally, we will test the efficacy of PTER or cabozantinib on metastasis initiating cells using xenograft, PDX and genetic mouse models (Aim 3). We believe that the outcome of our study will provide a paradigm shift in our current understanding of the pathology of brain metastasis and also have a significant impact on the future treatment of this devastating disease. The results of this study will significantly impact on this research field in three ways. First, we found that XIST plays a pivotal role in metastasis initiating cells in brain metastasis of breast cancer. XIST is known for its critical function for X inactivation and for modulation of pluripotency of embryonic stem cells; however, how this lncRNA is involved in tumor progression is virtually unknown. Therefore, the results of this project will reveal a novel pathological mechanism of tumor metastasis and provide a paradigm shift in our understanding of breast cancer progression. Secondly, we propose to decipher the pathway of reciprocal communication between metastasis initiating cells and astrocytes in the brain microenvironment and their roles in the metastatic progression, which we believe, will lead to a discovery of a novel therapeutic target. Finally, we will examine the potential utility of the natural compound, PTER, as a preventive and therapeutic measure for brain metastasis. We will also explore a possibility of PTER as a sensitizer of radiation therapy for the metastatic disease.


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 = -$42,606 )
2024	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	5	5/10/2024	NON-COMPETING CONTINUATION	-$42,606
														Subtotal = -$42,606

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	5	12/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $449,057 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	001	5	1/28/2021	NON-COMPETING CONTINUATION	$22,451
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	5	12/11/2020	NON-COMPETING CONTINUATION	$426,606
														Subtotal = $449,057

Issue Date FY: 2020 ( Subtotal = $449,057 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	4	12/16/2019	NON-COMPETING CONTINUATION	$404,151
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	001	4	1/14/2020	NON-COMPETING CONTINUATION	$44,906
														Subtotal = $449,057

Issue Date FY: 2019 ( Subtotal = $435,585 )
2019	2019	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	3	12/4/2018	NON-COMPETING CONTINUATION	$435,585
														Subtotal = $435,585

Issue Date FY: 2018 ( Subtotal = $449,057 )
2018	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	001	2	5/23/2018	NON-COMPETING CONTINUATION	$44,906
2018	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	2	12/21/2017	NON-COMPETING CONTINUATION	$404,151
														Subtotal = $449,057

Issue Date FY: 2017 ( Subtotal = $449,057 )
2017	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	1	12/7/2016	NEW	$449,057
														Subtotal = $449,057

Grand Total All Awards = $2,189,207

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Roles of long-non-coding RNA, XIST, in brain metastasis of breast cancer

Award Number: R01CA205067

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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