Comparative Analysis of Stk11/Lkb1 versus Pten Deficiency in Lung Adenocarcinoma Induced by CRISPR/Cas9.

Martin F Berthelsen,Martin K Thomsen,Mette A Pedersen,Justin V Joseph,Maria Riedel,Henrik Hager,Siv L Leknes,Mikkel H Vendelbo

doi:10.3390/cancers13050974

Martin F Berthelsen, Martin K Thomsen + Show 6 more

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https://doi.org/10.3390/cancers13050974

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Abstract

Simple SummaryLung cancer is by far the leading cause of cancer induced mortality worldwide with a median five-year survival rate of 19 percent. Genome sequencing of lung cancer samples has revealed several key mutated genes, which could be implicated in lung cancer formation. This study applied a mouse model of lung cancer based on CRISPR/Cas9 technology to functionally address key regulators of the mTor pathway, STK11 and PTEN. Our study revealed that loss of Stk11 drives lung adenocarcinoma progression, whereas Pten is dispensable. These functional mouse studies reveal that loss of Pten is non-essential for lung adenocarcinoma, which is in agreement with the low mutation rates of PTEN in human adenocarcinoma. In contrast, loss of Stk11 drive tumor progression and is often found mutated in human samples of lung adenocarcinoma.This study focused on STK11, PTEN, KRAS, and TP53, which are often found to be mutated in lung cancer. We compared Stk11 and Pten implication in lung cancer in combination with loss of Trp53 and gain of function of Kras in a CRISPR/Cas9 mouse model. Mice with loss of Stk11, Trp53, and KrasG12D mutation (SKT) reached human endpoint at around four months post-initiation. In comparison, mice with loss of Pten, Trp53, and KrasG12D mutation (PKT) survived six months or longer post-initiation. Pathological examination revealed an increase in proliferation in SKT deficient lung epithelia compared to PKT. This difference was independent of Pten loss, indicating that loss of Pten is dispensable for cell proliferation in lung adenocarcinoma. Furthermore, tumors with loss of Stk11, Trp53, and KrasG12D mutation had a significantly higher progression rate, monitored by PET/MRI scanning, compared to mice with loss of Pten, Trp53, and KrasG12D mutation, revealing that mutations in Stk11 are essential for adenocarcinoma progression. Overall, by using the CRISPR/Cas9 mouse model of lung adenocarcinoma, we showed that mutations in Stk11 are a key driver, whereas loss of Pten is dispensable for adenocarcinoma progression.

Highlights

This article is an open access article detection and treatment of lung cancer have significantly improved over recent decades, this malignancy is responsible for most cancer related mortality worldwide [1]
Loss of STK11 often co-occurs with gain-offunction mutations of KRAS, whereas loss of PTEN rarely occurs with activation of KRAS
The data set revealed that STK11, PTEN, TP53, and KRAS were mutated in between nine and 68 percent of lung cancers, with TP53 mutations

Summary

Introduction

This article is an open access article detection and treatment of lung cancer have significantly improved over recent decades, this malignancy is responsible for most cancer related mortality worldwide [1]. A variety of key mutated genes have been associated with subtypes of lung cancer. Among these are the tumor suppressor genes PTEN and STK11/LKB1. Both genes are directly involved in the negative regulation of the mTOR pathway, which induces cell transformation when constitutively activated. PTEN regulates the pathway by inhibiting the phosphorylation of AKT, which activates mTOR when phosphorylated [3]. STK11 negatively regulates the mTOR pathway by activation of AMPK [4]. Mutations of STK11 are more frequently found in lung cancer than loss of PTEN, indicating discrepancy in the molecular mechanism [5,6]. Loss of STK11 often co-occurs with gain-offunction mutations of KRAS, whereas loss of PTEN rarely occurs with activation of KRAS

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