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Comparative Analysis of Stk11/Lkb1 versus Pten Deficiency in Lung Adenocarcinoma Induced by CRISPR/Cas9
Martin F Berthelsen1, Siv L Leknes2, Maria Riedel1
1Department of Clinical Medicine, Aarhus University, DK-8200 Aarhus N, Denmark.
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.
Insights
Mutations in STK11 are key drivers of lung adenocarcinoma progression, while PTEN loss is dispensable. A CRISPR/Cas9 mouse model revealed STK11 mutations accelerate tumor growth compared to PTEN mutations.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Lung adenocarcinoma is frequently associated with mutations in STK11, PTEN, KRAS, and TP53.
- Understanding the interplay of these genetic alterations is crucial for developing targeted therapies.
Purpose of the Study:
- To compare the roles of STK11 and PTEN loss in lung adenocarcinoma development and progression.
- To investigate the combined effects of STK11/PTEN loss with TP53 loss and KRAS activation in a preclinical model.
Main Methods:
- Utilized a CRISPR/Cas9 genome editing system in mice to model specific genetic mutations found in lung cancer.
- Generated mouse models with distinct genetic backgrounds: STK11, TP53 loss, and KRASG12D activation (SKT) versus PTEN, TP53 loss, and KRASG12D activation (PKT).
- Assessed tumor progression using pathological examination and longitudinal PET/MRI imaging.
Main Results:
- Mice with SKT mutations exhibited significantly accelerated tumor progression and shorter survival times compared to PKT mice.
- Increased proliferation was observed in SKT-deficient lung epithelia, independent of PTEN status, suggesting PTEN loss is not essential for proliferation.
- PET/MRI monitoring revealed a higher progression rate in tumors with STK11 mutations, highlighting STK11's critical role.
Conclusions:
- STK11 mutations are a primary driver of lung adenocarcinoma progression.
- Loss of PTEN is dispensable for adenocarcinoma progression in the context of concurrent TP53 loss and KRAS activation.
- The CRISPR/Cas9 mouse model provides valuable insights into the distinct roles of STK11 and PTEN in lung cancer pathogenesis.
