Abstract 7470: Leukemia inhibitory factor promotes tumor progression in KRAS-driven lung cancer
Authors: Hanafi Imene Boukhalfa , Miller-Phillips Lisa , Zakraoui Ons , Marini Kieren D. , Umetsu Sarah , Wang Man-Tzu , Collisson Eric A. 
Published: March 2024

Leukemia inhibitory factor (LIF) displays complex effects in different types of cancer but its role in lung cancer remains unknown. Since KRAS mutation is an initial validated oncogenic event in near 30% of non-small cell lung cancer (PanCancer Atlas), we were interested in studying how LIF would influence tumor initiation and progression in KRAS-driven lung cancer.To properly study the roles of LIF throughout KRAS-driven tumorigenesis, we generated a novel genetically engineered mouse model (GEMM), where expression of LIF can be conditionally knocked out by Cre recombinase. Conditional deletion of the Lif allele in oncogenic KRAS-induced lung tumors is achieved by crossing Lif flox/flox mice with KrasLSL-G12D/+, Trp53flox/flox (KP) mouse model. In our lung cancer model, induction of oncogenic KRAS and depletion of LIF is attained through intratracheal infection of adeno-Cre virus.When our Lif flox/floxKP (LKP) and KP mice were infected by adeno-Cre virus, they developed lung tumors at reasonable frequencies within 4-8 months. We generated cell lines from tumors and used ELISA and RT-qPCR analysis to validate the efficiency of the knockout. While control KP tumor cell lines (n=3) showed Lif expression and LIF protein secretion, cell lines from LKP tumors (n=3) presented with undetectable Lif expression and no LIF secretion validating the successful deletion of Lif and functionality of our new mouse model. We generated H&E slides from the tumors and with the help of our pathologist we confirmed the subtype of lung adenocarcinoma. The effects of LIF on cell lines proliferation were evaluated in vitro and we found that LKP cell lines grow significantly slower than the KP lines (p&lt;0.05).Mice in both groups were monitored for their overall survival (OS) rate. LKP mice (n=5) tend to have an increased median overall survival at 176 days when compared to control KP mice (n=7) at 152 days (p=0.07). To estimate the tumor initiation and progression, mice in each group were sacrificed at early endpoints (10- and 15-weeks post adeno-cre infection) and ratios of lung weight/mouse weight were measured as an indicator of tumor burden. At 10 weeks, LKP mice (n=5) presented with significantly smaller ratios with an average of 0.014 compared to KP animals (n=4) with an average of 0.019 (p=0.027).We found that LIF tends to shorten overall survival and augments tumor burden in lung cancer. These data suggest that LIF has a pro-tumorigenic role in KRAS-driven lung cancer proposing this cytokine as a potential prognostic biomarker and its depletion as a promising therapeutic target.

Citation Format: Imene Boukhalfa Hanafi, Lisa Miller-Phillips, Ons Zakraoui, Kieren D. Marini, Sarah Umetsu, Man-Tzu Wang, Eric A. Collisson. Leukemia inhibitory factor promotes tumor progression in KRAS-driven lung 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 7470.