Dataset Information

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

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.

SUBMITTER: Molina ER

PROVIDER: S-EPMC8906536 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

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

Molina Eric R ER Chim Letitia K LK Lamhamedi-Cherradi Salah-Eddine SE Mohiuddin Sana S McCall David D Cuglievan Branko B Krishnan Sandhya S Porter Robert W RW Ingram Davis R DR Wang Wei-Lien WL Lazar Alexander J AJ Scott David W DW Truong Danh D DD Daw Najat C NC Ludwig Joseph A JA Mikos Antonios G AG

Oncotarget 20220309

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 ...[more]

PMID: 35284040

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Project description:Current in vitro methods for assessing cancer biology and therapeutic response rely heavily on monolayer cell culture on hard, plastic surfaces that do not recapitulate essential elements of the tumor microenvironment. While a host of tumor models exist, most are not engineered to control the physical properties of the microenvironment and thus may not reflect the effects of mechanotransduction on tumor biology. Utilizing coaxial electrospinning, we developed three-dimensional (3D) tumor models with tunable mechanical properties in order to elucidate the effects of substrate stiffness and tissue architecture in osteosarcoma. Mechanical properties of coaxial electrospun meshes were characterized with a series of macroscale testing with uniaxial tensile testing and microscale testing utilizing atomic force microscopy on single fibers. Calculated moduli in our models ranged over three orders of magnitude in both macroscale and microscale testing. Osteosarcoma cells responded to decreasing substrate stiffness in 3D environments by increasing nuclear localization of Hippo pathway effectors, YAP and TAZ, while downregulating total YAP. Additionally, a downregulation of the IGF-1R/mTOR axis, the target of recent clinical trials in sarcoma, was observed in 3D models and heralded increased resistance to combination chemotherapy and IGF-1R/mTOR targeted agents compared to monolayer controls. In this study, we highlight the necessity of incorporating mechanical cues in cancer biology investigation and the complexity in mechanotransduction as a confluence of stiffness and culture architecture. Our models provide a versatile, mechanically variable substrate on which to study the effects of physical cues on the pathogenesis of tumors. STATEMENT OF SIGNIFICANCE: The tumor microenvironment plays a critical role in cancer pathogenesis. In this work, we engineered 3D, mechanically tunable, coaxial electrospun environments to determine the roles of the mechanical environment on osteosarcoma cell phenotype, morphology, and therapeutic response. We characterize the effects of varying macroscale and microscale stiffnesses in 3D environments on the localization and expression of the mechanoresponsive proteins, YAP and TAZ, and evaluate IGF-1R/mTOR pathway activation, a target of recent clinical trials in sarcoma. Increased nuclear YAP/TAZ was observed as stiffness in 3D was decreased. Downregulation of the IGF-1R/mTOR cascade in all 3D environments was observed. Our study highlights the complexity of mechanotransduction in 3D culture and represents a step towards controlling microenvironmental elements in in vitro cancer investigations.

Project description:Primary bone tumor, also known as osteosarcoma (OS), is the most common primary malignancy of bone in children and young adults. Current treatment protocols yield a 5-year survival rate of near 70% although approximately 80% of patients have metastatic disease at the time of diagnosis. However, long-term survival rates have remained virtually unchanged for nearly four decades, largely due to our limited understanding of the disease process. One major signaling pathway that has been implicated in human OS tumorigenesis is the insulin-like growth factor (IGF)/insulin-like growth factor-1 receptor (IGF1R) signaling axis. IGF1R is a heterotetrameric α2β2 receptor, in which the α subunits comprise the ligand binding site, whereas the β subunits are transmembrane proteins containing intracellular tyrosine kinase domains. Although numerous strategies have been devised to target IGF/IGF1R axis, most of them have failed in clinical trials due to the lack of specificity and/or limited efficacy. Here, we investigated whether a more effective and specific blockade of IGF1R activity in human OS cells can be accomplished by employing dominant-negative IGF1R (dnIGF1R) mutants. We engineered the recombinant adenoviruses expressing two IGF1R mutants derived from the α (aa 1-524) and β (aa 741-936) subunits, and found that either dnIGF1Rα and/or dnIGF1Rβ effectively inhibited cell migration, colony formation, and cell cycle progression of human OS cells, which could be reversed by exogenous IGF1. Furthermore, dnIGF1Rα and/or dnIGF1Rβ inhibited OS xenograft tumor growth in vivo, with the greatest inhibition of tumor growth shown by dnIGF1Rα. Mechanistically, the dnIGF1R mutants down-regulated the expression of PI3K/AKT and RAS/RAF/MAPK, BCL2, Cyclin D1 and most EMT regulators, while up-regulating pro-apoptotic genes in human OS cells. Collectively, these findings strongly suggest that the dnIGF1R mutants, especially dnIGF1Rα, may be further developed as novel anticancer agents that target IGF signaling axis with high specificity and efficacy.

Dataset Information

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

Publications

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

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