Vav1 accelerates Ras-driven lung cancer and modulates its tumor microenvironment.

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The 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.

Original languageAmerican English
Article number110395
JournalCellular Signalling
Volume97
DOIs
StatePublished - Sep 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • ERK
  • K-Ras
  • Lung Cancer
  • Vav1

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