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The Role of RHOA in Diffuse Gastric Cancer

Award Number: R01CA224428
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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The Role of RHOA in Diffuse Gastric Cancer - PROJECT SUMMARY This project focuses upon Diffuse Gastric Cancer (DGC), a frequently lethal cancer, marked by its characteristic growth patterns with lack of cellular cohesion, highly invasive spread and marked propensity for metastasis. This proposal builds upon new progress in the study of DGC, bringing together a collaborative team of investigators with provocative new findings regarding the role of RHOA in the pathogenesis of this disease and several newly developed mouse model systems. These data and resources bring new opportunities to substantively advance the study of these deadly and understudied cancers. A first set of data underlying this application followed our recent identification of a novel stem cell population in gastric glands marked by Mist1 expression (Yokoyama et al, Cancer Cell 2015). These cells were demonstrated to give rise to DGC following engineered loss of tumor suppressor Cdh1. However, development of DGC required the secretion of Wnt5a by cells in the stem cell niche, with Wnt5a acting by activating GTPase RhoA in the Cdh1- null gastric cells. In parallel, we made a set of novel genomic discoveries, finding that ~20- 30% of DGCs harbor genomic aberrations impacting RHOA, either highly recurrent missense mutations of RHOA or a recurrent fusion gene including ARHGAP26, a RHOA regulator (TCGA, Nature, 2014). In this context, delineating the functions of RhoA in DGC pathogenesis, spanning both the role of Wild-type RHOA following Cdh1 loss and the oncogenic functions of RHOA mutations, emerge as critical paths towards the identification of therapeutic targets and understanding of basic pathophysiology of DGC formation. In our first Aim, we evaluate activation of wild-type RHOA in normal gastric corpus stem cells, and in early progression of Cdh1- deficient diffuse gastric cancer. We propose to test our hypothesis that RHOA is a mediator of Wnt5a effects upon corpus stem cells, especially following Cdh1 loss. These results will have immediate relevance to the definition of mechanisms of DGC initiation, clearly informing efforts to prevent and treat these deadly cancers. Our second aim evaluates RHOA somatic mutations in the initiation and progression of diffuse gastric cancer. In this aim we further characterize the biochemical and phenotypic effects of highly recurrent missense mutations of the RHOA GTPase identified in DGC. We will also functionally validate which RHOA effectors are essential for oncogenic activity of these mutants in both in vitro and in vivo systems, including our novel DGC mouse model driven by Cdh1 loss and RhoA mutation. Through these studies we hope to determine mechanisms of RHOA mediated transformation and identify specific pathways that are critical to the pathogenesis of DGC, findings with immediate potential relevance to the development of new therapeutic targets.


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 = -$27 )
2024	2022	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Microbiology and Infectious Diseases Research	000	5	10/13/2023	NON-COMPETING CONTINUATION	-$27
														Subtotal = -$27

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Microbiology and Infectious Diseases Research	000	5	1/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $787,791 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Microbiology and Infectious Diseases Research	000	5	3/14/2022	NON-COMPETING CONTINUATION	$723,480
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Microbiology and Infectious Diseases Research	001	5	5/4/2022	NON-COMPETING CONTINUATION	$64,311
														Subtotal = $787,791

Issue Date FY: 2021 ( Subtotal = $819,369 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Microbiology and Infectious Diseases Research	001	4	6/2/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$819,369
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Microbiology and Infectious Diseases Research	003	4	7/23/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$110,560
2021	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	3	5/31/2021	NON-COMPETING CONTINUATION	$0
2021	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	002	3	7/23/2021	NON-COMPETING CONTINUATION	-$110,560
														Subtotal = $819,369

Issue Date FY: 2020 ( Subtotal = $677,302 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	3	3/12/2020	NON-COMPETING CONTINUATION	$677,302
														Subtotal = $677,302

Issue Date FY: 2019 ( Subtotal = $656,983 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	2	3/29/2019	NON-COMPETING CONTINUATION	$656,983
														Subtotal = $656,983

Issue Date FY: 2018 ( Subtotal = $677,302 )
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	1	6/8/2018	NEW	$715,552
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	001	1	8/22/2018	NEW	-$38,250
														Subtotal = $677,302

Grand Total All Awards = $3,618,720

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The Role of RHOA in Diffuse Gastric Cancer

Award Number: R01CA224428

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/08/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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