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Dual localization of angiopoietin like protein 4 in the extracellular milieu and nucleus regulates the hematogenous brain metastasis of triple negative breast cancer

Award Number: R15CA287303
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Dual localization of angiopoietin like protein 4 in the extracellular milieu and nucleus regulates the hematogenous brain metastasis of triple negative breast cancer - Patients diagnosed with triple negative breast cancer (TNBC) brain metastasis face an uphill battle toward remission. Brain metastasis leads to cerebral edema, headaches, seizures, and motor and speech impairment, significantly impacting the patient’s quality of life during the treatment process. Nearly 80% of patients diagnosed with metastatic TNBC fail to live past a year post diagnosis despite therapeutic treatments. It is critical that brain metastasis drivers are identified so that crucial advancements to remedial chemotherapies can be developed. Here, our central hypothesis is that angiopoietin like protein 4 (ANGPTL4), dependent upon its location, regulates two pathways that facilitate hematogenous dissemination and TNBC brain metastasis growth: (1) chromatin-bound ANGPTL4 and Aurora Kinase A (AURKA) regulate anchorage independence and cell cycle arrest that facilitates hematogenous dissemination and (2) secreted ANGPTL4 through its association with integrins regulate anchorage dependent extravasation and formation of the blood-tumor barrier. The overall objective is to determine the functional consequences of secreted and nuclear ANGPTL4 on TNBC brain metastases; to strengthen the biomedical research environment at Arkansas State University; and to provide undergraduate students experience in cutting edge biomedical research to broaden their range of career choices. Our goal is to utilize a combination of genome editing of human TNBC cells, human genetically engineered TNBC cells, and TNBC xenografts to determine the functional consequences of nuclear ANGPTL4 on hematogenous dissemination of TNBC to the brain, characterize the mechanistic link between secreted ANGPTL4 and the formation of the blood-tumor barrier, and determine the synergistic effects of ANGPTL4 and AURKA antagonists on TNBC brain metastasis. Polymerase chain reaction-based site directed mutagenesis will be used to generate ANGPTL4 mutants for evaluating the functional consequences of nuclear ANGPTL4 on hematogenous dissemination of TNBC to the brain. shRNA mediated silencing of integrins in TNBC cells that overexpress wildtype ANGPTL4, secretory secretion mutants, or control vectors to modulate TNBC cell attachment to the brain vascular endothelial membrane will identify the mechanistic link between secreted ANGPTL4 and the formation of the blood-tumor barrier. Athymic nude mice will be injected via the left heart ventricle with TNBC cells that overexpressing ANGPTL4mGFP or mGFP to form brain metastases. This model will be used to determine whether ANGPTL4 and AURKA inhibitors synergistically regress TNBC brain metastases. We anticipate that upon completing this project, we will understand the necessity of nuclear ANGPTL4 for the anchorage independence and mitotic arrest required for hematogenous dissemination; the autocrine and paracrine function of ANGPTL4 on blood-tumor barrier formation and blood-brain barrier extravasation; and the efficacy of ANGPTL4 and AURKA antagonists on TNBC brain metastases. These crucial results will facilitate development of future remedial therapies.


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 = $408,259 )
2025	2025	ARKANSAS STATE UNIVERSITY	2105 AGGIE ROAD	JONESBORO	AR	72401	CRAIGHEAD	USA	Cancer Biology Research	000	1	8/19/2025	NEW	$408,259
														Subtotal = $408,259

Grand Total All Awards = $408,259

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Dual localization of angiopoietin like protein 4 in the extracellular milieu and nucleus regulates the hematogenous brain metastasis of triple negative breast cancer

Award Number: R15CA287303

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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