Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice

Yaser Salaymeh; Marganit Farago; Shulamit Sebban; Batel Shalom; Eli Pikarsky; Shulamit Katzav

doi:10.26508/lsa.202000661

Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice

Yaser Salaymeh, Marganit Farago, Shulamit Sebban, Batel Shalom, Eli Pikarsky, Shulamit Katzav^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

To explore the contribution of Vav1, a hematopoietic signal transducer, to pancreatic ductal adenocarcinoma (PDAC) development, we generated transgenic mouse lines expressing, Vav1, K-Ras^G12D, or both K-Ras^G12D and Vav1 in pancreatic acinar cells. Co-expression of Vav1 and K-Ras^G12D synergistically enhanced acinar-to-ductal metaplasia (ADM) formation, far exceeding the number of lesions developed in K-Ras^G12D mice. Mice expressing only Vav1 did not develop ADM. Moreover, the incidence of PDAC in K-Ras^G12D/ Vav1 was significantly higher than in K-Ras^G12D mice. Discontinuing Vav1 expression in K-Ras^G12D/Vav1 mice elicited a marked regression of malignant lesions in the pancreas, demonstrating Vav1 is required for generation and maintenance of ADM. Rac1-GTP levels in the K-Ras^G12D/Vav1 mice pancreas clearly demonstrated an increase in Rac1 activity. Treatment of K-Ras^G12D and K-Ras^G12D/Vav1 mice with azathioprine, an immune-suppressor drug which inhibits Vav1's activity as a GDP/GTP exchange factor, dramatically reduced the number of malignant lesions. These results suggest that Vav1 plays a role in the development of PDAC when co-expressed with K-Ras^G12D via its activity as a GEF for Rac1GTPase.

Original language	American English
Article number	e202000661
Journal	Life Science Alliance
Volume	3
Issue number	5
DOIs	https://doi.org/10.26508/lsa.202000661
State	Published - May 2020

Bibliographical note

Funding Information:
We are indebted to Shirley Smith for editing the manuscript and to Dr Dror Gal, Prof. Ittai Ben-Porath, and Prof. Yuval Dor for advice on mouse manipulation. This work was supported, in part, by grants from the Israel Academy of Sciences, the Israel Cancer Association (ICA) with the generous assistance of the USA Friends of ICA in Honor of Laurence Holzman and Felicia Needleman; The Israel Cancer Research Fund; The Hubert H Humphrey Center for Experimental Medicine and Cancer Research; The Alex U Soyka Pancreatic Cancer Research Project; and a donation from Vibeke Lichten.

Publisher Copyright:
© 2020 Salaymeh et al.

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title = "Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice",

abstract = "To explore the contribution of Vav1, a hematopoietic signal transducer, to pancreatic ductal adenocarcinoma (PDAC) development, we generated transgenic mouse lines expressing, Vav1, K-RasG12D, or both K-RasG12D and Vav1 in pancreatic acinar cells. Co-expression of Vav1 and K-RasG12D synergistically enhanced acinar-to-ductal metaplasia (ADM) formation, far exceeding the number of lesions developed in K-RasG12D mice. Mice expressing only Vav1 did not develop ADM. Moreover, the incidence of PDAC in K-RasG12D/ Vav1 was significantly higher than in K-RasG12D mice. Discontinuing Vav1 expression in K-RasG12D/Vav1 mice elicited a marked regression of malignant lesions in the pancreas, demonstrating Vav1 is required for generation and maintenance of ADM. Rac1-GTP levels in the K-RasG12D/Vav1 mice pancreas clearly demonstrated an increase in Rac1 activity. Treatment of K-RasG12D and K-RasG12D/Vav1 mice with azathioprine, an immune-suppressor drug which inhibits Vav1's activity as a GDP/GTP exchange factor, dramatically reduced the number of malignant lesions. These results suggest that Vav1 plays a role in the development of PDAC when co-expressed with K-RasG12D via its activity as a GEF for Rac1GTPase.",

author = "Yaser Salaymeh and Marganit Farago and Shulamit Sebban and Batel Shalom and Eli Pikarsky and Shulamit Katzav",

note = "Funding Information: We are indebted to Shirley Smith for editing the manuscript and to Dr Dror Gal, Prof. Ittai Ben-Porath, and Prof. Yuval Dor for advice on mouse manipulation. This work was supported, in part, by grants from the Israel Academy of Sciences, the Israel Cancer Association (ICA) with the generous assistance of the USA Friends of ICA in Honor of Laurence Holzman and Felicia Needleman; The Israel Cancer Research Fund; The Hubert H Humphrey Center for Experimental Medicine and Cancer Research; The Alex U Soyka Pancreatic Cancer Research Project; and a donation from Vibeke Lichten. Publisher Copyright: {\textcopyright} 2020 Salaymeh et al.",

year = "2020",

month = may,

doi = "10.26508/lsa.202000661",

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journal = "Life Science Alliance",

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T1 - Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice

AU - Salaymeh, Yaser

AU - Farago, Marganit

AU - Sebban, Shulamit

AU - Shalom, Batel

AU - Pikarsky, Eli

AU - Katzav, Shulamit

N1 - Funding Information: We are indebted to Shirley Smith for editing the manuscript and to Dr Dror Gal, Prof. Ittai Ben-Porath, and Prof. Yuval Dor for advice on mouse manipulation. This work was supported, in part, by grants from the Israel Academy of Sciences, the Israel Cancer Association (ICA) with the generous assistance of the USA Friends of ICA in Honor of Laurence Holzman and Felicia Needleman; The Israel Cancer Research Fund; The Hubert H Humphrey Center for Experimental Medicine and Cancer Research; The Alex U Soyka Pancreatic Cancer Research Project; and a donation from Vibeke Lichten. Publisher Copyright: © 2020 Salaymeh et al.

PY - 2020/5

Y1 - 2020/5

N2 - To explore the contribution of Vav1, a hematopoietic signal transducer, to pancreatic ductal adenocarcinoma (PDAC) development, we generated transgenic mouse lines expressing, Vav1, K-RasG12D, or both K-RasG12D and Vav1 in pancreatic acinar cells. Co-expression of Vav1 and K-RasG12D synergistically enhanced acinar-to-ductal metaplasia (ADM) formation, far exceeding the number of lesions developed in K-RasG12D mice. Mice expressing only Vav1 did not develop ADM. Moreover, the incidence of PDAC in K-RasG12D/ Vav1 was significantly higher than in K-RasG12D mice. Discontinuing Vav1 expression in K-RasG12D/Vav1 mice elicited a marked regression of malignant lesions in the pancreas, demonstrating Vav1 is required for generation and maintenance of ADM. Rac1-GTP levels in the K-RasG12D/Vav1 mice pancreas clearly demonstrated an increase in Rac1 activity. Treatment of K-RasG12D and K-RasG12D/Vav1 mice with azathioprine, an immune-suppressor drug which inhibits Vav1's activity as a GDP/GTP exchange factor, dramatically reduced the number of malignant lesions. These results suggest that Vav1 plays a role in the development of PDAC when co-expressed with K-RasG12D via its activity as a GEF for Rac1GTPase.

AB - To explore the contribution of Vav1, a hematopoietic signal transducer, to pancreatic ductal adenocarcinoma (PDAC) development, we generated transgenic mouse lines expressing, Vav1, K-RasG12D, or both K-RasG12D and Vav1 in pancreatic acinar cells. Co-expression of Vav1 and K-RasG12D synergistically enhanced acinar-to-ductal metaplasia (ADM) formation, far exceeding the number of lesions developed in K-RasG12D mice. Mice expressing only Vav1 did not develop ADM. Moreover, the incidence of PDAC in K-RasG12D/ Vav1 was significantly higher than in K-RasG12D mice. Discontinuing Vav1 expression in K-RasG12D/Vav1 mice elicited a marked regression of malignant lesions in the pancreas, demonstrating Vav1 is required for generation and maintenance of ADM. Rac1-GTP levels in the K-RasG12D/Vav1 mice pancreas clearly demonstrated an increase in Rac1 activity. Treatment of K-RasG12D and K-RasG12D/Vav1 mice with azathioprine, an immune-suppressor drug which inhibits Vav1's activity as a GDP/GTP exchange factor, dramatically reduced the number of malignant lesions. These results suggest that Vav1 plays a role in the development of PDAC when co-expressed with K-RasG12D via its activity as a GEF for Rac1GTPase.

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DO - 10.26508/lsa.202000661

M3 - Article

C2 - 32277014

AN - SCOPUS:85083195473

SN - 2575-1077

VL - 3

JO - Life Science Alliance

JF - Life Science Alliance

IS - 5

M1 - e202000661

ER -

Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice

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