Combining molecular characteristics and therapeutic analysis of PDOs predict clinical responses and guide PDAC personalized treatment.

Abstract

Background: The emergence of targeted therapies and immunotherapy has broadened treatment options for patients with pancreatic ductal adenocarcinoma (PDAC). Despite this, traditional drug selection, predominantly relies on tumor markers and clinical staging, has underutilized these drugs due to ignoring patient genomic diversity. Patient-derived organoids (PDOs) and corresponding patient-derived organoid xenograft (PDOX) models offer a way to better understand and address this.

Methods: In this study, we established PDOs and PDOX models from PDAC clinical samples. These models were analyzed using immunohistochemistry, H&E staining, and genomic profiling. Drug screening with 111 FDA-approved drugs was performed on PDOs, and drug responses in PDOs and PDOX models were compared to assess consistency with clinical treatment outcomes. Gene analysis was conducted to explore the molecular mechanisms underlying variations in drug responses. Additionally, by analyzing the sequencing results from various drug-sensitive groups, the identified differential gene-drug metabolism gene UGT1A10 were modulated in PDOs to evaluate its impact on drug efficacy. A co-culture system of PDOs with immune cells was developed to study the efficacy of immunotherapies.

Results: PDOs and matched PDOX models retain the morphological, biological, and genomic characteristics of the primary tumor. Exome sequencing and RNA sequencing confirmed both the consistency and heterogeneity among the PDOs. High-throughput drug screening revealed significant variability in drug sensitivity across different organoids, yet PDOs and PDOX derived from the same patient exhibited a high degree of concordance in response to clinical chemotherapy agents. The gene expression analysis of PDOs with significant differences in drug sensitivity revealed UGT1A10 as a crucial regulator. The knockdown of UGT1A10 notably increased drug sensitivity. Furthermore, immune cells demonstrated specific cytotoxicity towards the organoids, underscoring the potential of the co-culture system for application in tumor immunotherapy.

Conclusion: Our results highlight the necessity for personalized treatment strategies that consider genomic diversity beyond tumor markers, thus validating the utility of PDOs and PDOX models in advancing PDAC research and personalized medicine.