Batel Shalom, Marganit Farago, Yaser Salaymeh, Shulamit Sebban, Matan Risling, Eli Pikarsky, Shulamit Katzav
Cellular signalling 2022 SepThe potential impact of Vav1 on human cancer was only recently acknowledged, as it is detected as a mutant or an overexpressed gene in various cancers, including lung cancer. Vav1, which is normally and exclusively expressed in the hematopoietic system functions as a specific GDP/GTP nucleotide exchange factor (GEF), strictly regulated by tyrosine phosphorylation. To investigate whether Vav1 plays a causative or facilitating role in-vivo in lung cancer development and to examine whether it co-operates with other oncogenes, such as mutant K-Ras, we generated novel mouse strains that express: Vav1 or K-RasG12D in type II pneumocytes, as well as a transgenic mouse line that expresses both Vav1 and K-RasG12D in these cells. Coexpression of Vav1 and K-RasG12D in the lungs dramatically increased malignant lung cancer lesions, and did so significantly faster than K-RasG12D alone, strongly suggesting that these two oncogenes synergize to enhance lung tumor development. Vav1 expression alone had no apparent effects on lung tumorigenesis. The increase in lung cancer in K-RasG12D/Vav1 mice was accompanied by an increase in B-cell, T-cells, and monocyte infiltration in the tumor microenvironment. Concomitantly, ERK phosphorylation was highly elevated in the lungs of K-RasG12 D/Vav1 mice. Also, several cytokines such as IL-4 and IL-13 which play a significant role in the immune system, were elevated in lungs of Vav1 and K-RasG12 D/Vav1 mice. Our findings emphasize the contribution of Vav1 to lung tumor development through its signaling properties. Copyright © 2022 Elsevier Inc. All rights reserved.
Batel Shalom, Marganit Farago, Yaser Salaymeh, Shulamit Sebban, Matan Risling, Eli Pikarsky, Shulamit Katzav. Vav1 accelerates Ras-driven lung cancer and modulates its tumor microenvironment. Cellular signalling. 2022 Sep;97:110395
PMID: 35752351
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