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In vivo optical metabolic imaging of long-chain fatty acid uptake in orthotopic models of triple negative breast cancer

View ORCID ProfileMegan C. Madonna, Joy E. Duer, View ORCID ProfileJoyce V. Lee, Jeremy Williams, Baris Avsaroglu, View ORCID ProfileCaigang Zhu, Riley Deutsch, Roujia Wang, View ORCID ProfileBrian T. Crouch, View ORCID ProfileMatthew D Hirschey, View ORCID ProfileAndrei Goga, View ORCID ProfileNirmala Ramanujam
doi: https://doi.org/10.1101/2020.11.02.365288
Megan C. Madonna
1Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
1Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
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  • For correspondence: megan.madonna@duke.edu
Joy E. Duer
2Duke University Trinity College of Arts and Sciences, Durham, NC 27708, USA
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Joyce V. Lee
3Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, 94143, USA
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Jeremy Williams
3Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, 94143, USA
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Baris Avsaroglu
3Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, 94143, USA
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Caigang Zhu
1Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
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Riley Deutsch
1Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
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Roujia Wang
1Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
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Brian T. Crouch
1Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
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Matthew D Hirschey
4Duke Molecular Physiology Institute, Durham, NC, 27701, USA
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Andrei Goga
3Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, 94143, USA
5Department of Medicine, University of California, San Francisco, San Francisco, California, 94143, USA
6Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, 94143, USA
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Nirmala Ramanujam
1Department of Biomedical Engineering, Duke University, Durham, NC, 27708 USA
7Department of Pharmacology & Cancer Biology, School of Medicine, Duke University, Durham, NC, 27708 USA
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Abstract

Targeting a tumor’s metabolic dependencies is a clinically actionable therapeutic approach, but identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breast cancer. Imaging techniques offer the opportunity to quantify nutrient use in preclinical models to aid in the development of new drugs to restrict uptake or utilization of these nutrients. We describe a fast and dynamic approach to image fatty acid uptake in vivo, a tool relevant to study tumor metabolic reprogramming or for studying the effectiveness of drugs targeting lipid metabolism spanning beyond breast cancer and optical imaging alone. Specifically, we developed a quantitative optical approach to spatially and longitudinally map the kinetics of long-chain fatty acid uptake in in vivo murine models of breast cancer using a fluorescently labeled palmitate molecule, Bodipy FL c16. We chose intra-vital microscopy of mammary tumor windows to validate our approach in two orthotopic breast cancer models: a MYC-overexpressing transgenic triple-negative breast cancer (TNBC) model and a murine model of the 4T1 family. Following injection, Bodipy FL c16 fluorescence increased and reached its maximum after approximately 30 minutes, with the signal remaining stable during the 30-80-minute post-injection period. We used the fluorescence at 60 minutes (Bodipy60), the mid-point in the plateau region, as a summary parameter to quantify Bodipy FL c16 fluorescence in subsequent experiments. Using our imaging platform, we observed a two- to four-fold decrease in fatty acid uptake in response to the downregulation of the MYC oncogene consistent with findings from in vitro metabolic assays. In contrast, our imaging studies report an increase in fatty acid uptake with tumor aggressiveness (6NR, 4T07, and 4T1), and uptake was significantly decreased after treatment with a fatty acid transport inhibitor, perphenazine, in both normal mammary pads and in the most aggressive 4T1 tumor model. Our approach fills an important gap between in vitro assays, which provide rich metabolic information but at static time points, and imaging approaches that can visualize metabolism in whole organs, but which suffer from poor resolution.

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 02, 2020.
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In vivo optical metabolic imaging of long-chain fatty acid uptake in orthotopic models of triple negative breast cancer
Megan C. Madonna, Joy E. Duer, Joyce V. Lee, Jeremy Williams, Baris Avsaroglu, Caigang Zhu, Riley Deutsch, Roujia Wang, Brian T. Crouch, Matthew D Hirschey, Andrei Goga, Nirmala Ramanujam
bioRxiv 2020.11.02.365288; doi: https://doi.org/10.1101/2020.11.02.365288
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In vivo optical metabolic imaging of long-chain fatty acid uptake in orthotopic models of triple negative breast cancer
Megan C. Madonna, Joy E. Duer, Joyce V. Lee, Jeremy Williams, Baris Avsaroglu, Caigang Zhu, Riley Deutsch, Roujia Wang, Brian T. Crouch, Matthew D Hirschey, Andrei Goga, Nirmala Ramanujam
bioRxiv 2020.11.02.365288; doi: https://doi.org/10.1101/2020.11.02.365288

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