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Biophysical Interrogation of Signals that Drive GBM Invasion

Award Number: R01NS116802
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Biophysical Interrogation of Signals that Drive GBM Invasion - One major issue confounding successful treatment of glioblastoma multiforme (GBM) is the presence of highly invasive cells disseminating into the brain parenchyma. These cells evade surgical resection and often spread distally in brain parenchyma. Multiple and spatially distinct heterotypic populations exist within a single GBM, giving rise to the disease’s genetic heterogeneity and leading to complex cell intrinsic and extrinsic mechanisms of invasion. Amplification of the epidermal growth factor receptor (EGFR), a hallmark mutation present in 60% of cases, most often occurs in a heterogeneous manner and is frequently associated with deletion of exons 2-7, creating a constitutively active mutant, EGFRvIII. While significant focus has been placed on its kinase activity, comparatively little is known about EGFRvIII’s ability to enhance migration via interaction with adhesion receptors. Our preliminary data supports a dual role for EGFRvIII where it interferes with intrinsic adhesion receptors and also recruits non-transformed counterparts via extrinsic signaling to reduce adhesion of a mixed population. Based on our findings, we hypothesize that this difference in adhesive activity is due to differential signaling associated with EGFRvIII, and that this receptor conveys this phenotype to non-transformed counterparts through cytokine production (Inda, Genes & Dev, 2010; Zanca, Genes & Dev, 2017) to cooperatively invade parenchyma. With this hypothesis, we will use adhesion measurement technologies to dissect cell intrinsic EGFR-mediated invasion mechanisms; given the heterogeneity within tumors, we will also combine newly developed adhesion sorting technologies with high throughput sequencing technologies to identify cell extrinsic mechanisms and targets for subsequent intervention. The following lines of experimentation will be carried out: 1) implementation of biophysical assays and signaling pathway analyses to interrogate how cell intrinsic activity of EGFRvIII leads to labile adhesion and an invasive phenotype; 2) biochemical and functional analysis of the EGFRvIII cell extrinsic, secretome-mediated education of wtEGFR cell adhesive phenotype; 3) expression and epigenetic analyses on adhesion-sorted populations will be used to define a migratome signature, its stability in wtEGFR cells after exposure to the EGFRvIII secretome, and the ability of “educated” wtEGFR to propagate that epigenetic signature to naïve wtEGFR cells.


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 = -$51,631 )
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/24/2025	NON-COMPETING CONTINUATION	-$51,631
														Subtotal = -$51,631

Issue Date FY: 2024 ( Subtotal = $417,510 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/20/2024	NON-COMPETING CONTINUATION	$417,510
														Subtotal = $417,510

Issue Date FY: 2023 ( Subtotal = $491,568 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/5/2023	NON-COMPETING CONTINUATION	$467,311
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/6/2023	SUPPLEMENT FOR EXPANSION	$24,257
														Subtotal = $491,568

Issue Date FY: 2022 ( Subtotal = $528,747 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/8/2022	SUPPLEMENT FOR EXPANSION	$91,436
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/7/2022	NON-COMPETING CONTINUATION	$467,311
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	4/13/2022	SUPPLEMENT FOR EXPANSION	-$30,000
														Subtotal = $528,747

Issue Date FY: 2021 ( Subtotal = $460,729 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/14/2021	SUPPLEMENT FOR EXPANSION	$49,598
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/19/2021	NON-COMPETING CONTINUATION	$411,131
														Subtotal = $460,729

Issue Date FY: 2020 ( Subtotal = $425,140 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/29/2020	NEW	$425,140
														Subtotal = $425,140

Grand Total All Awards = $2,272,063

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Biophysical Interrogation of Signals that Drive GBM Invasion

Award Number: R01NS116802

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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