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Comparative analysis of Stk11/Lkb1 versus Pten deficiency in lung adenocarcinoma induced by CRISPR/Cas9

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This study focused on STK11, PTEN, KRAS, and TP53, which are often found to be mu-tated 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-initia-tion. 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, indi-cating 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.

OriginalsprogEngelsk
Artikelnummer974
TidsskriftCancers
Vol/bind13
Nummer5
Antal sider13
ISSN2072-6694
DOI
StatusUdgivet - feb. 2021

Bibliografisk note

Funding Information:
Funding: This research was funded by AUFF NOVA (AUFF-E-2015-FLS-9-8), Danish Cancer Society (R146-A9394), Aage og Johanne Louis-Hansen’s fund, Fabricant Einar Willumsens memorial fund, Director Emil C. Hertz and wife Inger Hertz’s fund, Helge Peetz and Verner and wife Vilma Peetz’s fund, Karen Elise Jensen’s fund and from The Aarhus University Research Foundation, Denmark. M.F.B. was co-funded by The Graduate School of Health, Aarhus University.

Funding Information:
This research was funded by AUFF NOVA (AUFF-E-2015-FLS-9-8), Danish Cancer Society (R146-A9394), Aage og Johanne Louis-Hansen?s fund, Fabricant Einar Willumsens memorial fund, Director Emil C. Hertz and wife Inger Hertz?s fund, Helge Peetz and Verner and wife Vilma Peetz?s fund, Karen Elise Jensen?s fund and from The Aarhus University Research Foundation, Denmark. M.F.B. was co-funded by The Graduate School of Health, Aarhus University. We would like to thank Mette I.T. Simonsen for her aid with the microPET/MR scanning of the mice, Charlotte K?rsgaard and Rolf Bue Kloster for technical assistance, and Kristoffer K. Augustesen for taking care of our mice. We would also like to thank Dirk Grimm?s laboratory, especially Anne-Kathrin Herrmann for teaching M.F.B. to produce and purify AAV.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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