Oncotarget

Research Papers:

Correlation of nuclear pIGF-1R/IGF-1R and YAP/TAZ in a tissue microarray with outcomes in osteosarcoma patients

Eric R. Molina, Letitia K. Chim, Salah-Eddine Lamhamedi-Cherradi, Sana Mohiuddin, David McCall, Branko Cuglievan, Sandhya Krishnan, Robert W. Porter, Davis R. Ingram, Wei-Lien Wang, Alexander J. Lazar, David W. Scott, Danh D. Truong, Najat C. Daw, Joseph A. Ludwig _ and Antonios G. Mikos _

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Oncotarget. 2022; 13:521-533. https://doi.org/10.18632/oncotarget.28215

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Abstract

Eric R. Molina1, Letitia K. Chim2, Salah-Eddine Lamhamedi-Cherradi1, Sana Mohiuddin1, David McCall3, Branko Cuglievan3, Sandhya Krishnan1, Robert W. Porter1, Davis R. Ingram4, Wei-Lien Wang4, Alexander J. Lazar4,5, David W. Scott6, Danh D. Truong1, Najat C. Daw3, Joseph A. Ludwig1 and Antonios G. Mikos2

1 Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

2 Department of Bioengineering, Rice University, Houston, TX, USA

3 Division of Pediatrics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

4 Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

5 Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

6 Department of Statistics, Rice University, Houston, TX, USA

Correspondence to:

Joseph A. Ludwig, email: jaludwig@mdanderson.org
Antonios G. Mikos, email: mikos@rice.edu

Keywords: osteosarcoma; YAP/TAZ; IGF-1R; nuclear IGF-1R; mechanotransduction

Received: November 17, 2021     Accepted: February 24, 2022     Published: March 09, 2022

Copyright: © 2022 Molina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Osteosarcoma (OS) is a genetically diverse bone cancer that lacks a consistent targetable mutation. Recent studies suggest the IGF/PI3K/mTOR pathway and YAP/TAZ paralogs regulate cell fate and proliferation in response to biomechanical cues within the tumor microenvironment. How this occurs and their implication upon osteosarcoma survival, remains poorly understood.

Here, we show that IGF-1R can translocate into the nucleus, where it may act as part of a transcription factor complex. To explore the relationship between YAP/TAZ and total and nuclear phosphorylated IGF-1R (pIGF-1R), we evaluated sequential tumor sections from a 37-patient tissue microarray by confocal microscopy. Next, we examined the relationship between stained markers, clinical disease characteristics, and patient outcomes. The nuclear to cytoplasmic ratios (N:C ratio) of YAP and TAZ strongly correlated with nuclear pIGF-1R (r = 0.522, p = 0.001 for each pair). Kaplan–Meier analyses indicated that nuclear pIGF-1R predicted poor overall survival, a finding confirmed in the Cox proportional hazards model.

Though additional investigation in a larger prospective study will be required to validate the prognostic accuracy of these markers, our results may have broad implications for the new class of YAP, TAZ, AXL, or TEAD inhibitors that have reached early phase clinical trials this year.


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