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ResearchIn-Press PreviewGastroenterologyOncology Open Access | 10.1172/JCI186035

LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models

Alice E. Shin,1 Kensuke Sugiura,1 Secunda W. Kariuki,1 David A. Cohen,2 Samuel P. Flashner,1 Andres J. Klein-Szanto,3 Noriyuki Nishiwaki,1 Dechokyab De,1 Neil Vasan,4 Joel T. Gabre,1 Christopher J. Lengner,5 Peter A. Sims,6 and Anil K. Rustgi1

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Shin, A. in: JCI | PubMed | Google Scholar |

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Sugiura, K. in: JCI | PubMed | Google Scholar |

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Kariuki, S. in: JCI | PubMed | Google Scholar

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Cohen, D. in: JCI | PubMed | Google Scholar

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Flashner, S. in: JCI | PubMed | Google Scholar

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Klein-Szanto, A. in: JCI | PubMed | Google Scholar |

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Nishiwaki, N. in: JCI | PubMed | Google Scholar

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by De, D. in: JCI | PubMed | Google Scholar

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Vasan, N. in: JCI | PubMed | Google Scholar

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Gabre, J. in: JCI | PubMed | Google Scholar

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Lengner, C. in: JCI | PubMed | Google Scholar |

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Sims, P. in: JCI | PubMed | Google Scholar

1Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

2Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

3Histopathology Facility, Fox Chase Cancer Center, Philadelphia, United States of America

4Division of Hematology and Oncology, Department of Medicine, Herbert Irving, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

5Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States of America

Find articles by Rustgi, A. in: JCI | PubMed | Google Scholar

Published January 14, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186035.
Copyright © 2025, Shin et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 14, 2025 - Version history
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Abstract

Colorectal cancer (CRC) remains a leading cause of cancer death due to metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present the first comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (an S6K inhibitor) in CRC cell lines and mouse- and patient-derived organoids (PDOs). Tissue microarrays from CRC patients confirmed that LIN28B and PI3K/AKT pathway activation correlate with CRC progression. These findings highlight the critical role of the LIN28B-mediated PI3K/AKT pathway in CRC metastasis, the therapeutic potential of targeted inhibition, and the promise of PDOs in precision medicine in metastatic CRC.

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