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NIR Bioluminescence Probe Enables Discovery of Diet-Induced Modulation of the Tumor Microenvironment via Nitric Oxide

preprint
submitted on 08.03.2021, 01:11 and posted on 09.03.2021, 06:17 by Anuj K Yadav, Michael C. Lee, Melissa Lucero, Christopher J. Reinhardt, ShengZhang Su, Jefferson Chan

Nitric oxide (NO) plays a critical role in acute and chronic inflammation. NO’s contributions to cancer are of particular interest due to its context-dependent bioactivities. For example, immune cells initially produce cytotoxic quantities of NO in response to the nascent tumor. However, it is believed that this fades over time and reaches a concentration that supports the tumor microenvironment (TME). These complex dynamics are further complicated by other factors, such as diet and oxygenation, making it challenging to establish a complete picture of NO’s impact on tumor progression. Although many activity-based sensing (ABS) probes for NO have been developed, only a small fraction have been employed in vivo and fewer yet are practical in cancer models where the NO concentration is < 200 nM. To overcome this outstanding challenge, we have developed BL660-NO, the first ABS probe for NIR bioluminescence imaging of NO in cancer. Owing to the low intrinsic background, high sensitivity, and deep tissue imaging capabilities of our design, BL660-NO was successfully employed to visualize endogenous NO in cellular systems, a human liver metastasis model, and a murine breast cancer model. Importantly, its exceptional performance facilitated the design of a dietary study to examine the impact of NO on the TME by varying the intake of fat. BL660-NO provides the first direct molecular evidence that intratumoral NO becomes elevated in mice fed a high-fat diet who became obese with larger tumors compared to control animals on a low-fat diet. These results indicate that an inflammatory diet can increase NO production via recruitment of macrophages and overexpression of iNOS which in turn can drive tumor progression.

Funding

Chemical Tools to Study the Role of Biological Aldehydes

National Institute of General Medical Sciences

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History

Email Address of Submitting Author

jeffchan@illinois.edu

Institution

University of Illinois at Urbana-Champaign

Country

United States

ORCID For Submitting Author

0000-0003-4139-4379

Declaration of Conflict of Interest

No conflict of Interest

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