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- Title
Spatial Alignment of Organoids Tracking Subclonal Chemotherapy Resistance in Pancreatic and Ampullary Cancer.
- Authors
Hossan, Md Shahadat; Lin, Ethan Samuel; Riedl, Eleanor; Stram, Austin; Mehlhaff, Eric; Koeppel, Luke; Warner, Jamie; Uko, Inem; Mankowski Gettle, Lori; Lubner, Sam; McGregor, Stephanie M.; Zhang, Wei; Murphy, William; Kratz, Jeremy D.
- Abstract
Pancreatic and ampullary cancers remain highly morbid diseases for which accurate clinical predictions are needed for precise therapeutic predictions. Patient-derived cancer organoids have been widely adopted; however, prior work has focused on well-level therapeutic sensitivity. To characterize individual oligoclonal units of therapeutic response, we introduce a low-volume screening assay, including an automated alignment algorithm. The oligoclonal growth response was compared against validated markers of response, including well-level viability and markers of single-cell viability. Line-specific sensitivities were compared with clinical outcomes. Automated alignment algorithms were generated to match organoids across time using coordinates across a single projection of Z-stacked images. After screening for baseline size (50 μm) and circularity (>0.4), the match efficiency was found to be optimized by accepting the diffusion thresholded with the root mean standard deviation of 75 μm. Validated well-level viability showed a limited correlation with the mean organoid size (R = 0.408), and a normalized growth assayed by normalized changes in area (R = 0.474) and area (R = 0.486). Subclonal populations were defined by both residual growth and the failure to induce apoptosis and necrosis. For a culture with clinical resistance to gemcitabine and nab-paclitaxel, while a therapeutic challenge induced a robust effect in inhibiting cell growth (GΔ = 1.53), residual oligoclonal populations were able to limit the effect on the ability to induce apoptosis (GΔ = 0.52) and cell necrosis (GΔ = 1.07). Bioengineered approaches are feasible to capture oligoclonal heterogeneity in organotypic cultures, integrating ongoing efforts for utilizing organoids across cancer types as integral biomarkers and in novel therapeutic development.
- Subjects
BILIARY tract cancer; PANCREATIC cancer; ORGANOIDS; CANCER chemotherapy; CELL growth
- Publication
Bioengineering (Basel), 2023, Vol 10, Issue 1, p91
- ISSN
2306-5354
- Publication type
Article
- DOI
10.3390/bioengineering10010091