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Illuminating Dynamic Receptor Clustering in the Epidermal Growth Factor Receptor Signal Transduction Pathway Using Plasmon Coupling

Award Number: R01CA138509
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2009
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Illuminating Dynamic Receptor Clustering in the Epidermal Growth Factor Receptor Signal Transduction Pathway Using Plasmon Coupling - SUMMARY The epidermal growth factor receptor (EGFR) is a model tyrosine kinase whose overexpression is common in various cancers, including basal-like breast cancer (BLBC). It is becoming increasingly clear that EGFR underlies not only conventional biochemical regulation induced by ligand-receptor binding but also much less well understood spatial and temporal regulation mechanisms. A heterogeneous distribution of the receptor at the plasma membrane results in an enrichment of EGFR in membrane regions with lateral dimensions of tens to hundreds of nanometers where receptor dimerization and oligomerization is favored due to a high local concentration of receptors. These clusters are not static but undergo continuous structural fluctuations. The relationship between this dynamic structure and the local signaling activation are insufficiently understood, partly because of a lack of appropriate optical tools for mapping subdiffraction limit dynamics with high temporal bandwidth and long observation time. Aim 1 of this application takes advantage of the unique photophysical properties of plasmonic nanoparticles (NPs) that provide large and stable optical signals and also encode information about deeply subdiffraction limit separations between NPs in their far-field spectrum to characterize the lateral diffusion and structural dynamics of individual EGFR clusters with high temporal resolution and without physical limitation in observation time. Previous implementations of plasmon coupling microscopy (PCM) utilized the NP spectrum detected under darkfield illumination to identify EGFR clustering. Dark-field detection requires, however, large (~40 nm) NP labels. In Aim 1, we will implement a new interferometric PCM (iPCM) for detecting 5 nm (to probe EGFR-EGFR contacts) and 10 nm (to probe EGFR oligomerization and clustering) gold NP labels. iPCM will be augmented with a correlation analysis to quantify continuous fluctuations in plasmon coupling. This technology will be applied to test the hypothesis that EGF binding results in a decrease of intracluster dynamics and an increase in EGFR phosphorylation. Another insufficiently understood element of structural regulation that is associated with EGFR clustering is lateral signal propagation through inter-receptor contacts or EGF-induced second messenger release. Aim 2 will elucidate how EGFR clustering impacts NP-EGF-induced reactive oxygen species (ROS) formation and ROS-mediated EGFR activation. In this approach EGF-functionalized NPs (NP- EGF) with known EGF loading are not simple imaging tools for mapping sub-diffraction limit clusters of EGFR, but instead, represent quantifiably units of local EGFR activation. In Aim 3 nanoconjugated EGF will be applied as probe to quantify the cross-talk between EGFR activation and nitric oxide (NO) formation. As NO synthesis is spatially and temporally strictly regulated, its concentration depends on EGFR activation, which varies as function of the local NP-EGF concentration. Aim 3 will test the hypothesis that NP-EGF-induced NO generation is a regulatory factor for c-Jun N-terminal kinase (JNK)-mediated apoptosis in BLBC 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: 2024 ( Subtotal = $372,281 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	15	4/30/2024	NON-COMPETING CONTINUATION	$372,281
														Subtotal = $372,281

Issue Date FY: 2023 ( Subtotal = $465,501 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	14	3/20/2023	SUPPLEMENT FOR EXPANSION	$73,626
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	14	3/17/2023	NON-COMPETING CONTINUATION	$391,875
														Subtotal = $465,501

Issue Date FY: 2022 ( Subtotal = $456,191 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	13	4/15/2022	NON-COMPETING CONTINUATION	$384,038
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	002	13	8/24/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	13	4/19/2022	SUPPLEMENT FOR EXPANSION	$72,153
														Subtotal = $456,191

Issue Date FY: 2021 ( Subtotal = $433,307 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	12	9/21/2021	SUPPLEMENT FOR EXPANSION	$56,869
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	12	3/23/2021	NON-COMPETING CONTINUATION	$376,438
														Subtotal = $433,307

Issue Date FY: 2020 ( Subtotal = $364,088 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	003	11	7/31/2020	COMPETING CONTINUATION	$36,310
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	11	3/10/2020	COMPETING CONTINUATION	$364,088
2020	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	002	10	7/31/2020	NON-COMPETING CONTINUATION	-$36,310
2020	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	10	3/10/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $364,088

Issue Date FY: 2018 ( Subtotal = $368,325 )
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	10	4/26/2018	NON-COMPETING CONTINUATION	$368,325
														Subtotal = $368,325

Issue Date FY: 2017 ( Subtotal = $368,325 )
2017	2017	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	9	6/7/2017	NON-COMPETING CONTINUATION	$36,833
2017	2017	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	9	4/27/2017	NON-COMPETING CONTINUATION	$331,492
														Subtotal = $368,325

Issue Date FY: 2016 ( Subtotal = $368,325 )
2016	2016	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	8	5/3/2016	NON-COMPETING CONTINUATION	$368,325
														Subtotal = $368,325

Issue Date FY: 2015 ( Subtotal = $368,325 )
2015	2015	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	7	3/18/2015	NON-COMPETING CONTINUATION	$368,325
														Subtotal = $368,325

Issue Date FY: 2014 ( Subtotal = $349,215 )
2014	2014	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	6	2/13/2014	COMPETING CONTINUATION	$293,649
2014	2014	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	6	6/4/2014	COMPETING CONTINUATION	$55,566
														Subtotal = $349,215

Issue Date FY: 2013 ( Subtotal = $307,448 )
2013	2013	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	5	5/1/2013	NON-COMPETING CONTINUATION	$76,863
2013	2013	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	5	6/26/2013	NON-COMPETING CONTINUATION	$230,585
														Subtotal = $307,448

Issue Date FY: 2012 ( Subtotal = $327,072 )
2012	2012	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	4	3/15/2012	NON-COMPETING CONTINUATION	$327,072
														Subtotal = $327,072

Issue Date FY: 2011 ( Subtotal = $327,072 )
2011	2011	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	3	5/16/2011	NON-COMPETING CONTINUATION	$23,603
2011	2011	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	3	3/7/2011	NON-COMPETING CONTINUATION	$303,469
														Subtotal = $327,072

Issue Date FY: 2010 ( Subtotal = $337,188 )
2010	2010	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	2	3/31/2010	NON-COMPETING CONTINUATION	$337,188
														Subtotal = $337,188

Issue Date FY: 2009 ( Subtotal = $306,063 )
2009	2009	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	1	5/19/2009	NEW	$306,063
														Subtotal = $306,063

Grand Total All Awards = $5,518,726

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Illuminating Dynamic Receptor Clustering in the Epidermal Growth Factor Receptor Signal Transduction Pathway Using Plasmon Coupling

Award Number: R01CA138509

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2009

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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