Abstract 5374: Novel mouse models to study the role of the docking protein GAB2 in general and in cancer
Authors: Angel Moritz , Klappstein Vanessa , Schrimpf Jule , Langhammer Melanie , Shoumariyeh Khalid , Miething Cornelius , Kloz Ulrich , Armstrong Brittney , van der Hoeven Franciscus , Brummer Tilman , Halbach Sebastian 
Published: March 2024

Abstract
The docking protein GAB2 binds to growth factor, cytokine and antigen receptors via the adaptor GRB2. Thereby, GAB2 amplifies the signaling output of the SHP2/Ras/ERK, PI3K/AKT and STAT5 pathways, leading to survival, proliferation and migration. Beside these physiological functions, GAB2 is often overexpressed or hyperphosphorylated in different types of cancer, in particular melanoma, breast cancer and various leukemia entities. Previous studies demonstrated that mice with constitutive Gab2 deficiency are protected against breast cancer, acute and chronic myeloid leukemia driven by HER2, BCR::ABL1 and FLT3-ITD, respectively. While these studies support a critical role in tumor initiation, nothing is known about the relevance of GAB2 for tumor maintenance and progression. To this end, we have developed two novel conditional loss- and gain-of-function mouse models to further analyze the role of GAB2 in cancer.
In the first model, the transgenic GAB2 mouse, GAB2 is expressed under the control of the TET-O promotor, allowing the tetracycline dependent expression in tissues expressing a tetracycline trans activator (tTA). We have already started by crossing in the SCLtTA mouse, in which tTA is expressed under the control of the murine stem cell leukemia 3’ enhancer. Here we show that the expression of transgenic GAB2 is tightly regulated by tetracycline and restricted to hematopoietic cells. This system is now perfectly suited to analyze the role of GAB2 in hematologic malignancies. By expressing tTA under different promotors, we propose that GAB2 overexpression can be directed to other organs or cell types. Combining this mouse line with cancer mouse models will allow to study the role of GAB2 in different cancer entities.
With the second mouse model, the conditional Gab2 KO mouse, it is possible to study the therapeutic potential of GAB2 impairment in vivo. In this mouse, exon three of the Gab2 gene is flanked by LoxP sites. This allows for its CRE recombinase mediated deletion, leading to GAB2 deficiency. The combination of this mouse model with inducible and tissue specific CRE strains will allow to analyze the role of GAB2 in various cancer mouse models. To demonstrate the efficient conditional deletion of exon 3, we first crossed in the tamoxifen inducible ROSA26 CreERT2 mouse line. So far, we were able to show the functionality of this system in vitro in mouse embryonic fibroblasts (MEFs) generated from the conditional Gab2 KO mouse. In a next step we will verify the results in vivo and will cross this mouse line with a mouse model for Chronic Myeloid Leukemia (CML) to investigate the therapeutic potential of GAB2 in CML.
In summary, we are convinced that these two novel mouse models will help to identify GAB2 as a potential target or biomarker in various cancer entities. In particular, the conditional approach will allow to alter GAB2 expression in already established tumors, thus mimicking pharmacological targeting.
Citation Format: Moritz Angel, Vanessa Klappstein, Jule Schrimpf, Melanie Langhammer, Khalid Shoumariyeh, Cornelius Miething, Ulrich Kloz, Brittney Armstrong, Franciscus van der Hoeven, Tilman Brummer, Sebastian Halbach. Novel mouse models to study the role of the docking protein GAB2 in general and in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5374.