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Interstitial Fluid Flow Regulates Glioma Cell Invasion

Award Number: R37CA222563
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Interstitial Fluid Flow Regulates Glioma Cell Invasion - Project Summary Glioblastoma, the deadliest form of brain cancer, is defined by the invasive nature of its cells. Invasion in the brain follows distinctive routes that correlate with interstitial and bulk flow pathways. In brain cancer, increased interstitial fluid flow develops due to the increase in interstitial pressure in the tumor bulk interfacing with the relatively normal pressure of the surrounding brain tissue, or tumor microenvironment. This differential leads to fluid transport specifically across the invasive edge of the tumor where cells are prone to both interact with the surrounding brain tissue and to evade localized, transport-limited therapies. To examine how interstitial fluid flow affects the invasion of brain cancer cells, we have developed in vitro and in vivo methods to examine fluid flow responses. In vitro, we have found that interstitial flow enhances invasion of brain cancer cells using both cell lines and patient-derived glioma stem cells in tissue-engineered models of the brain-tumor interface via the chemokine/receptor pair CXCL12/CXCR4. In vivo, we have seen interstitial flow and increase invasion of implanted cancer cells through the brain in part through this same mechanism. By conducting in vivo measurements of interstitial flow using MRI we have correlated regions of interstitial fluid flow, glioma invasion, and glial gene expression of the receptor sphingosine-1-phosphate 3. In this proposal, we will examine the role of interstitial fluid flow as a driving factor of glioma invasion. To make a case for the importance of interstitial flow in regulating GBM invasion first, we will elucidate the true nature of interstitial flow in the in vivo GBM microenvironment. We will accomplish this utilizing clinically relevant imaging and computational tools to probe the prevalence of flow as the tumor develops, and determine regions in which flow is the highest. Second, we will determine the contributions of interstitial flow at the level of cancer cell invasion. We will observe invasion patterns of multiple patient-derived glioblastoma stem cells in the specifically interrogating the mechanism of CXCR4/CXCL12-mediated autologous chemotaxis, a novel mechanism of invasion only possible under flow. Finally, we will use our unique ability to tissue engineer the glioblastoma microenvironment to examine the role of glial-expressed S1PR3 under flow on glioma invasion. Altogether, these reports will advance the importance and strategies for mitigating interstitial flow and its effects in GBM and offer modalities by which to study further effects of flow on therapeutic response. Understanding the impact of interstitial flow will ultimately help predict areas of GBM progression and recurrence. .


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 = -$9,240 )
2025	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	000	7	4/7/2025	NON-COMPETING CONTINUATION	-$9,240
														Subtotal = -$9,240

Issue Date FY: 2024 ( Subtotal = $508,646 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	004	7	4/17/2024	NON-COMPETING CONTINUATION	$26,769
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	002	7	11/7/2023	NON-COMPETING CONTINUATION	$481,877
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	003	7	11/29/2023	NON-COMPETING CONTINUATION	$0
2024	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	001	6	10/13/2023	EXTENSION WITH OR WITHOUT FUNDS	$105,058
2024	2022	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	000	5	10/13/2023	NON-COMPETING CONTINUATION	-$105,058
														Subtotal = $508,646

Issue Date FY: 2023 ( Subtotal = $525,316 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	000	6	2/1/2023	EXTENSION WITH OR WITHOUT FUNDS	$525,316
														Subtotal = $525,316

Issue Date FY: 2022 ( Subtotal = $486,846 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	001	5	4/27/2022	NON-COMPETING CONTINUATION	$48,686
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	000	5	11/4/2021	NON-COMPETING CONTINUATION	$438,160
														Subtotal = $486,846

Issue Date FY: 2021 ( Subtotal = $476,966 )
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	001	4	1/22/2021	NON-COMPETING CONTINUATION	$23,848
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	000	4	11/5/2020	NON-COMPETING CONTINUATION	$453,118
														Subtotal = $476,966

Issue Date FY: 2020 ( Subtotal = $526,024 )
2020	2020	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	001	3	1/16/2020	NON-COMPETING CONTINUATION	$52,602
2020	2020	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	000	3	11/18/2019	NON-COMPETING CONTINUATION	$473,422
														Subtotal = $526,024

Issue Date FY: 2019 ( Subtotal = $911,116 )
2019	2019	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Aging Research	001	2	8/8/2019	SUPPLEMENT FOR EXPANSION	$391,994
2019	2019	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	000	2	11/20/2018	NON-COMPETING CONTINUATION	$519,122
														Subtotal = $911,116

Issue Date FY: 2018 ( Subtotal = $575,131 )
2018	2018	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	001	1	7/16/2018	NEW	$0
2018	2018	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Detection and Diagnosis Research	000	1	12/13/2017	NEW	$575,131
														Subtotal = $575,131

Grand Total All Awards = $4,000,805

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Interstitial Fluid Flow Regulates Glioma Cell Invasion

Award Number: R37CA222563

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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