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Dynamic Ultrasound Molecular Targeted Imaging of Senescencein Evaluation of Lapatinib Resistance in HER2 Positive Breast Cancer

ABSTRACT: Prolonged treatment of HER2+ breast cancer cells with lapatinib (LAP) causes cellular senescence and acquired drug resistance, which often associating with poor prognosis for patients. We aim to explore the correlation between cellular senescence and LAP resistance in HER2+ breast cancer, screening for molecular marker of reversible senescence, and construct targeted nanobubbles for ultrasound molecular imaging and dynamically evaluate LAP resistance. In this study, we established a new cellular model of reversible cellular senescence using LAP and HER2+ breast cancer cells and found that reversible senescence contributed to LAP resistance in HER2+ breast cancer. Then we identified ecto-5'-nucleotidase (NT5E) as a marker of reversible senescence in HER2+ breast cancer. Based on this, we constructed NT5E targeted nanobubbles (NT5E-FITC-NBs) as a new molecular imaging modality which could both target reversible senescent cells and be used for ultrasound imaging. NT5E-FITC-NBs showed excellent physical and imaging characteristics. As an ultrasound contrast agent, NT5E-FITC-NBs could accurately identify reversible senescent cells both in vitro and in vivo. Our data demonstrate that cellular senescence-based ultrasound targeted imaging can identify reversible senescence and evaluate LAP resistance effectively in HER2+ breast cancer, which has the potential to improve cancer outcomes by altering treatment strategies ahead of aggressive recurrences.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237413 | GEO | 2024/07/14

REPOSITORIES: GEO

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Project description:The paper describes a model on the trastuzumab-induced immune response in murine(mouse) HER2+ breast cancer. Created by COPASI 4.25 (Build 207) This model is described in the article: Mathematical modelling of trastuzumab-induced immune response in an in vivo murine model of HER2+ breast cancer Angela M. Jarrett, Meghan J. Bloom, Wesley Godfrey, Anum K. Syed, David A. Ekrut, Lauren I. Ehrlich, Thomas E. Yankeelov, Anna G. Sorace Mathematical Medicine and Biology: A Journal of the IMA (2018) 00, 1–30 Abstract: The goal of this study is to develop an integrated, mathematical–experimental approach for understanding the interactions between the immune system and the effects of trastuzumab on breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2+). A system of coupled, ordinary differential equations was constructed to describe the temporal changes in tumour growth, along with intratumoural changes in the immune response, vascularity, necrosis and hypoxia. The mathematical model is calibrated with serially acquired experimental data of tumour volume, vascularity, necrosis and hypoxia obtained from either imaging or histology from a murine model of HER2+ breast cancer. Sensitivity analysis shows that model components are sensitive for 12 of 13 parameters, but accounting for uncertainty in the parameter values, model simulations still agree with the experimental data. Given theinitial conditions, the mathematical model predicts an increase in the immune infiltrates over time in the treated animals. Immunofluorescent staining results are presented that validate this prediction by showing an increased co-staining of CD11c and F4/80 (proteins expressed by dendritic cells and/or macrophages) in the total tissue for the treated tumours compared to the controls. We posit that the proposed mathematical–experimental approach can be used to elucidate driving interactions between the trastuzumab-induced responses in the tumour and the immune system that drive the stabilization of vasculature while simultaneously decreasing tumour growth—conclusions revealed by the mathematical model that were not deducible from the experimental data alone. This model is hosted on BioModels Database and identified by: MODEL1907050004. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Dynamic Ultrasound Molecular Targeted Imaging of Senescencein Evaluation of Lapatinib Resistance in HER2 Positive Breast Cancer

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