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Updated: Nov 7, 2025
A Human Cerebral Organoid Model of Neural Cell Transplantation
Published on: July 21, 2023
Autofluorescence Imaging of Treatment Response in Neuroendocrine Tumor Organoids
Amani A Gillette1, Christopher P Babiarz2, Ava R VanDommelen3
1Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53706, USA.
Abstract:
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.
Insights
Optical metabolic imaging (OMI) effectively measures drug response in patient-derived cancer organoids (PDCOs) for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This novel approach aids in developing targeted therapies for GEP-NET patients.
Area of Science:
- Oncology
- Biomedical Imaging
- Translational Medicine
Background:
- Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a significant subset of neuroendocrine tumors, often exhibiting low proliferation rates that challenge traditional drug response assessment.
- Existing animal models and cell lines poorly recapitulate the slow-growing nature of human GEP-NETs, limiting therapeutic development.
- Patient-derived cancer organoids (PDCOs) offer a promising 3D model for well-differentiated GEP-NETs, but conventional drug response metrics are inadequate due to small tissue volume and low cell division.
Purpose of the Study:
- To evaluate the efficacy of optical metabolic imaging (OMI) as a label-free, non-destructive method for assessing drug response in live GEP-NET PDCOs.
- To determine if OMI can detect drug responses in GEP-NET PDCOs to a novel combination therapy involving ABT263 (navitoclax) and everolimus.
- To explore the potential of OMI in identifying heterogeneous drug responses within GEP-NET PDCO populations.
Main Methods:
- Utilized two-photon optical metabolic imaging (OMI) to capture endogenous metabolic cofactor NAD(P)H and FAD fluorescence in live GEP-NET PDCOs.
- Tested the response of GEP-NET PDCO lines from seven patients to ABT263 (Bcl-2 inhibitor), everolimus (mTOR inhibitor), and their combination.
- Analyzed OMI data at 72 hours post-treatment to quantify metabolic changes indicative of drug response.
Main Results:
- OMI successfully measured drug response to the combination therapy in 5 out of 7 GEP-NET PDCO lines.
- Heterogeneous metabolic responses were identified in one non-responsive PDCO line, revealing distinct subpopulations.
- The study demonstrated OMI's capability to provide single-cell metabolic insights into drug efficacy in GEP-NET PDCOs.
Conclusions:
- Optical metabolic imaging is a viable and effective tool for assessing drug response in GEP-NET patient-derived cancer organoids.
- OMI can identify responders and non-responders to novel drug combinations, including potential for detecting metabolic heterogeneity.
- This technique holds significant promise for guiding personalized drug development and treatment strategies for gastroenteropancreatic neuroendocrine tumors.
