Abstract 2907: Extracellular matrix remodeling triggered by lysyl oxidase inhibition promote the lung adenocarcinoma to squamous cell carcinoma transition independent of LKB1 status
Authors: Yao Shun , Ji Hongbin 
Published: July 2017

Introduction: Lung adeno-squamous cell carcinoma represents as the most malignant subtype of non-small cell lung cancer. We have previously shown that Lkb1-deficiency triggered the lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC) transition (AST) in mice through extracellular matrix remodeling, in which lysyl oxidase (LOX) plays an important role. Considering the high frequency of P53 mutations in human lung cancer, we reason it's attractive to test if LOX inhibition could modulate the lung cancer plasticity and subtype transition independent of LKB1 status.Methods: KrasG12D/P53L/L (KP) mice were used to treat with BAPN or DPA,two LOX inhibitors, daily via intraperitoneal injection post 4 weeks of Adeno-Cre infection for 6-8 weeks and then harvested the lungs for pathological analyses. The histology and expression of related markers were analyzed by H&E, IHC staining, quantitative PCR and western blot. Results: BAPN/DPA treatment could result in a dramatic reduction of collagen deposition. We found no significant changes of total tumor number, but decreased average tumor size and tumor burden in treatment groups. Detailed pathological analyses showed that a few tumors from treatment group displayed typical squamous pathology, with the expression of squamous markers P63 and K14. In contrast, the tumors from control groups were adenomatous pathology and only expressing ADC markers TTF1 and SP-C. We further found that either BAPN or DPA treatment in KP mice promoted apoptosis and inhibited cell proliferation in ADC. Interestingly, we found the transited SCC showed almost no growth arrest and low apoptosis rate after BAPN or DPA treatment, indicative of the resistance to LOX inhibitors. ECM deprivation is a major cause of oxidative stress that contributes to the accumulation of reactive oxygen species (ROS) through the deregulation of certain metabolic pathways. We then checked the level of 8-hydroxydeoxyguanosine (8-oxo-dGuo), a marker of DNA oxidative modification by ROS. In treatment groups, 8-oxo-dGuo was significantly lower in SCC than ADC. In our previous work done in KL model, we found that the ROS level was significantly up-regulated by LKB1 inactivation, which functionally modulated the AST. However, in KP mouse model, either LKB1 or p-AMPK level showed no significant change with or without BAPN/DPA treatment.Conclusions: These data demonstrated that pharmacological LOX inhibition could trigger the ADC to SCC transition independent of LKB1 status, highlight a non-cancer-cell autonomous role in phenotypic transition. Moreover, this lineage transition confers lung cancer with strong survival capability under environmental stress as well as the acquisition of drug resistance.

Citation Format: Shun Yao, Hongbin Ji. Extracellular matrix remodeling triggered by lysyl oxidase inhibition promote the lung adenocarcinoma to squamous cell carcinoma transition independent of LKB1 status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2907. doi:10.1158/1538-7445.AM2017-2907