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Open AccessArticle

Autofluorescence Imaging of Treatment Response in Neuroendocrine Tumor Organoids

1
Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53706, USA
2
Department of Medicine, Division of Hematology, Oncology and Palliative Care, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
3
Morgridge Institute for Research, Madison, WI 53715, USA
4
University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA
5
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53705, USA
6
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53705, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Dario Livio Longo
Cancers 2021, 13(8), 1873; https://doi.org/10.3390/cancers13081873
Received: 5 March 2021 / Revised: 30 March 2021 / Accepted: 8 April 2021 / Published: 14 April 2021
(This article belongs to the Special Issue Imaging Cancer Metabolism)
Gastroenteropancreatic neuroendocrine tumors (GEP-NET) account for roughly 60% of all neuroendocrine tumors, and low/intermediate grade human GEP-NETs have relatively slow growth rates that many laboratory culture methods fail to capture. Patient-derived cancer organoids (PDCOs) are an attractive model to address this need for relevant 3D cultures of GEP-NETs for laboratory drug testing. However, traditional measurements of drug response are not effective in GEP-NET PDCOs due to the small volume of tissue and slow growth rates that are characteristic of the disease. Here, we test a label-free, non-destructive optical metabolic imaging (OMI) method to measure drug response in live GEP-NET PDCOs. OMI measured a response to the novel treatment combination of ABT-263 and everolimus in five out of seven PDCO lines, at 72 h post-treatment. Overall, this work shows that OMI provides single-cell metabolic measurements of drug response in PDCOs to guide drug development for GEP-NET patients.
Gastroenteropancreatic neuroendocrine tumors (GEP-NET) account for roughly 60% of all neuroendocrine tumors. Low/intermediate grade human GEP-NETs have relatively low proliferation rates that animal models and cell lines fail to recapitulate. Short-term patient-derived cancer organoids (PDCOs) are a 3D model system that holds great promise for recapitulating well-differentiated human GEP-NETs. However, traditional measurements of drug response (i.e., growth, proliferation) are not effective in GEP-NET PDCOs due to the small volume of tissue and low proliferation rates that are characteristic of the disease. Here, we test a label-free, non-destructive optical metabolic imaging (OMI) method to measure drug response in live GEP-NET PDCOs. OMI captures the fluorescence lifetime and intensity of endogenous metabolic cofactors NAD(P)H and FAD. OMI has previously provided accurate predictions of drug response on a single cell level in other cancer types, but this is the first study to apply OMI to GEP-NETs. OMI tested the response to novel drug combination on GEP-NET PDCOs, specifically ABT263 (navitoclax), a Bcl-2 family inhibitor, and everolimus, a standard GEP-NET treatment that inhibits mTOR. Treatment response to ABT263, everolimus, and the combination were tested in GEP-NET PDCO lines derived from seven patients, using two-photon OMI. OMI measured a response to the combination treatment in 5 PDCO lines, at 72 h post-treatment. In one of the non-responsive PDCO lines, heterogeneous response was identified with two distinct subpopulations of cell metabolism. Overall, this work shows that OMI provides single-cell metabolic measurements of drug response in PDCOs to guide drug development for GEP-NET patients. View Full-Text
Keywords: fluorescence lifetime imaging; NAD(P)H; autofluorescence; neuroendocrine tumor; organoid fluorescence lifetime imaging; NAD(P)H; autofluorescence; neuroendocrine tumor; organoid
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MDPI and ACS Style

Gillette, A.A.; Babiarz, C.P.; VanDommelen, A.R.; Pasch, C.A.; Clipson, L.; Matkowskyj, K.A.; Deming, D.A.; Skala, M.C. Autofluorescence Imaging of Treatment Response in Neuroendocrine Tumor Organoids. Cancers 2021, 13, 1873. https://doi.org/10.3390/cancers13081873

AMA Style

Gillette AA, Babiarz CP, VanDommelen AR, Pasch CA, Clipson L, Matkowskyj KA, Deming DA, Skala MC. Autofluorescence Imaging of Treatment Response in Neuroendocrine Tumor Organoids. Cancers. 2021; 13(8):1873. https://doi.org/10.3390/cancers13081873

Chicago/Turabian Style

Gillette, Amani A.; Babiarz, Christopher P.; VanDommelen, Ava R.; Pasch, Cheri A.; Clipson, Linda; Matkowskyj, Kristina A.; Deming, Dustin A.; Skala, Melissa C. 2021. "Autofluorescence Imaging of Treatment Response in Neuroendocrine Tumor Organoids" Cancers 13, no. 8: 1873. https://doi.org/10.3390/cancers13081873

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