Monitoring AKT activity and targeting in live tissue and disease contexts using a real-time Akt-FRET biosensor mouse-Reference-Cited by-同舟云学术

Monitoring AKT activity and targeting in live tissue and disease contexts using a real-time Akt-FRET biosensor mouse

Published:2023-04-28 Issue:17 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Conway James R. W.¹²³⁴^ORCID,Warren Sean C.¹²⁴^ORCID,Lee Young-Kyung¹⁴^ORCID,McCulloch Andrew T.¹⁴⁵,Magenau Astrid¹²⁴,Lee Victoria¹⁴^ORCID,Metcalf Xanthe L.¹⁴^ORCID,Stoehr Janett¹⁴^ORCID,Haigh Katharina⁶⁷,Abdulkhalek Lea¹⁴,Guaman Cristian S.¹⁴^ORCID,Reed Daniel A.¹⁴^ORCID,Murphy Kendelle J.¹²⁴^ORCID,Pereira Brooke A.¹²⁴^ORCID,Mélénec Pauline¹⁴^ORCID,Chambers Cecilia¹⁴^ORCID,Latham Sharissa L.¹²⁴^ORCID,Lenthall Helen¹,Deenick Elissa K.¹²^ORCID,Ma Yuanqing¹²^ORCID,Phan Tri¹²^ORCID,Lim Elgene¹²^ORCID,Joshua Anthony M.¹²^ORCID,Walters Stacey¹^ORCID,Grey Shane T.¹²^ORCID,Shi Yan-Chuan¹²^ORCID,Zhang Lei¹²^ORCID,Herzog Herbert¹²,Croucher David R.¹²⁴^ORCID,Philp Andy⁸⁹,Scheele Colinda L.G.J.¹⁰¹¹^ORCID,Herrmann David¹²⁴^ORCID,Sansom Owen J.¹²¹³^ORCID,Morton Jennifer P.¹²¹³^ORCID,Papa Antonella¹⁴^ORCID,Haigh Jody J.⁶⁷^ORCID,Nobis Max¹²⁴¹⁰¹⁵^ORCID,Timpson Paul¹²⁴^ORCID

Affiliation:

1. Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia.

2. St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia.

3. Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.

4. Cancer Ecosystems Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

5. School of Clinical Medicine, UNSW Sydney, Randwick Clinical Campus, Sydney, NSW, Australia.

6. Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.

7. CancerCare Manitoba Research Institute, Winnipeg, Manitoba, Canada.

8. School of Clinical Medicine, Randwick Clinical Campus, UNSW Sydney, Centre for Healthy Ageing, Centenary Institute, Missenden Road, Sydney, NSW 2050, Australia.

9. Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.

10. Laboratory for Intravital Imaging and Dynamics of Tumor Progression, VIB Center for Cancer Biology, KU Leuven, 3000 Leuven, Belgium.

11. Department of Oncology, KU Leuven, 3000 Leuven, Belgium.

12. Cancer Research UK Beatson Institute, Glasgow G611BD, UK.

13. School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G611QH, UK.

14. Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.

15. Intravital Imaging Expertise Center, VIB Center for Cancer Biology, KU Leuven, 3000 Leuven, Belgium.

Abstract

Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models. We also show that the dynamics of AKT activation can be monitored in real time in diverse tissues, including in individual islets of the pancreas, in the brown and white adipose tissue, and in the skeletal muscle. Thus, the Akt-FRET biosensor mouse provides an important tool to study AKT dynamics in live tissue contexts and has broad preclinical applications.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adf9063

Reference70 articles.

1. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation

2. The protein kinase B/Akt signalling pathway in human malignancy

3. Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine

4. Development of an optimized backbone of FRET biosensors for kinases and GTPases

5. Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer