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

Abstract

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.

Targeting AP-1 transcription factors by CRISPR in the prostate

“…Genetically engineered mouse models (GEMM) are essential to study gene function in PCa [6][7][8]. CRISPR/ Cas system has improved the gene editing toolbox in numerous in vivo models, with the murine system being the most prevalent [9,10]. We applied the CRISPR/Cas9 technology to study gene alterations in the murine prostate using orthotopic viral delivery of multiplexed sgRNAs, targeting multiple genes to evaluate their functions in PCa progression [11][12][13].…”

LKB1 Regulates Goat Intramuscular Adipogenesis Through Focal Adhesion Pathway

“…Liver kinase B1 (LKB1) also known as serine/threonine kinase 11 (STK11) is a serine/ threonine kinase (Berthelsen et al, 2021), which participates in the regulation of a variety of cellular physiological and pathological processes (Shan et al, 2016a,b;Xiong et al, 2017Xiong et al, , 2018b and phosphorylates 14 kinases of AMPK subfamily and regulates systemic glucose and energy balance (Lizcano et al, 2004). In skeletal muscle, LKB1 ablation exhibited a severe myopathy characterized by centrally nucleated myofibers, reduced mobility, growth retardation, and premature death (Shan et al, 2014), which is essential for the development and function of skeletal muscle (Shan et al, 2017).…”

The CRISPR/Cas9 Minipig—A Transgenic Minipig to Produce Specific Mutations in Designated Tissues

“…The lentivirus is integrated into the genome, unlike the AAV, which could accelerate cancer formation. Cancer induction in their pig model resembles tumour formation in a similar Cas9 mouse model, where we and others have shown cancer formation 3 months post transduction with AVV particles containing sgRNAs [ 19 , 20 ]. Multiple discrepancies between their and our model could explain the different outcomes.…”

“…The frequency of cancer in larger animals is similar or lower when compared to small animals, suggesting that large animals have evolved additional tumour suppressor functions [ 3 , 35 ]. We have compared mouse with porcine models by targeting the same genes in the pig that introduced lung cancer in mice by the use of the CRISPR/Cas9 technology [ 19 , 20 ]. The lack of cancer formation in the pig suggests a significant discrepancy between both models.…”

“…The method has multiple advantages, especially by simultaneous multiplex gene alteration in somatic cells. For example, lung cancer has been induced in mice by targeting Trp53 , Stk11 and Kras , followed by rapid cancer development [ 19 , 20 ].…”