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Volume 13
Issue 5
10.3390/cancers13050974
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Article

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

by
Martin F. Berthelsen
1,
Siv L. Leknes
2,
Maria Riedel
1,
Mette A. Pedersen
2,3,4,
Justin V. Joseph
1,
Henrik Hager
5,
Mikkel H. Vendelbo
2,3 and
Martin K. Thomsen
1,2,6,*
1
Department of Clinical Medicine, Aarhus University, DK-8200 Aarhus N, Denmark
2
Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark
3
Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, DK-8200 Aarhus N, Denmark
4
Steno Diabetes Center Aarhus, DK-8200 Aarhus N, Denmark
5
Department of Clinical Pathology, Vejle Hospital, Beriderbakken 4, DK-7100 Vejle, Denmark
6
Aarhus Institute of Advanced Studies (AIAS), Aarhus University, DK-8000 Aarhus, Denmark
*
Author to whom correspondence should be addressed.
Academic Editor: Myung-Ju Ahn
Cancers 2021, 13(5), 974; https://doi.org/10.3390/cancers13050974
Received: 11 December 2020 / Revised: 13 February 2021 / Accepted: 19 February 2021 / Published: 26 February 2021
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Simple Summary

Lung 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.

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. View Full-Text
Keywords: lung cancer; CRISPR; adenocarcinoma; mouse model; STK11; PTEN lung cancer; CRISPR; adenocarcinoma; mouse model; STK11; PTEN
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MDPI and ACS Style

Berthelsen, M.F.; Leknes, S.L.; Riedel, M.; Pedersen, M.A.; Joseph, J.V.; Hager, H.; Vendelbo, M.H.; Thomsen, M.K. Comparative Analysis of Stk11/Lkb1 versus Pten Deficiency in Lung Adenocarcinoma Induced by CRISPR/Cas9. Cancers 2021, 13, 974. https://doi.org/10.3390/cancers13050974

AMA Style

Berthelsen MF, Leknes SL, Riedel M, Pedersen MA, Joseph JV, Hager H, Vendelbo MH, Thomsen MK. Comparative Analysis of Stk11/Lkb1 versus Pten Deficiency in Lung Adenocarcinoma Induced by CRISPR/Cas9. Cancers. 2021; 13(5):974. https://doi.org/10.3390/cancers13050974

Chicago/Turabian Style

Berthelsen, Martin F., Siv L. Leknes, Maria Riedel, Mette A. Pedersen, Justin V. Joseph, Henrik Hager, Mikkel H. Vendelbo, and Martin K. Thomsen. 2021. "Comparative Analysis of Stk11/Lkb1 versus Pten Deficiency in Lung Adenocarcinoma Induced by CRISPR/Cas9" Cancers 13, no. 5: 974. https://doi.org/10.3390/cancers13050974

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