3D imaging analysis on an organoid-based platform guides personalized treatment in pancreatic ductal adenocarcinoma

Area of Science:

• Oncology
• Biotechnology
• Personalized Medicine

Background:

• Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges due to unpredictable chemotherapy responses and a lack of pre-treatment predictive assays.
• Current therapeutic strategies for PDAC often lack personalization, leading to suboptimal patient outcomes.
• The need for methods to assay patient tumors and identify effective treatment regimens based on individual tumor sensitivities is critical.

Purpose of the Study:

• To develop and validate an organoid-based platform (OBP) for quantifying patient-derived organoid (PDO) responses to drug treatments.
• To assess tumor-stroma modulation within PDOs as a potential biomarker for treatment efficacy.
• To correlate organoid-level findings with patient outcomes for personalized pancreatic cancer therapy.

Main Methods:

• Retrospective quantification of apoptotic responses and tumor-stroma cell proportions in PDOs using 3D immunofluorescence (Annexin A5, α-SMA, CK-19).
• Ex vivo organoid drug sensitivity assay (ODSA) to measure PDO responses to standard-of-care chemotherapy regimens.
• Statistical analysis, including exact McNemar's test and Kaplan-Meier survival analysis, to compare ODSA results with patient tumor responses and survival.

Main Results:

• The OBP successfully quantified immunofluorescence signals, organoid growth, and Ki-67 levels in PDOs over 14 days.
• ODSA drug responses showed no significant difference compared to patient tumor responses, as indicated by CA19-9 reductions post-neoadjuvant chemotherapy (P = 0.99).
• Distinct apoptotic and tumor-stroma modulation profiles were observed in PDOs (P < 0.0001). A high α-SMA/CK-19 ratio (>1.0) correlated with improved patient outcomes (P = 0.0179) and longer survival (P = 0.0046).

Conclusions:

• Patient-derived organoids exhibit heterogeneous apoptotic drug responses and tumor-stroma modulation following standard chemotherapy.
• The ratio of α-SMA to CK-19 levels in PDOs serves as a predictive biomarker for patient survival.
• The OBP holds promise for guiding personalized therapy selection to enhance systemic treatment efficacy in PDAC patients.