A Comprehensive Adenoid Cystic Carcinoma-Derived Organoid Platform for Disease Modeling and Drug Screening Captures Interpatient Heterogeneity

TL;DR

A new organoid platform for adenoid cystic carcinoma captures tumor diversity and enables fast drug testing.

Contribution

Development of a high-throughput ACC organoid platform that preserves tumor heterogeneity and enables rapid drug screening.

Findings

ACC organoids successfully recapitulate histopathological and genomic features of parental tumors.

The organoid platform enables high-throughput drug screening with an 88% success rate.

RNA and protein analyses confirm the presence of key tumor markers and cellular components in ACC organoids.

Abstract

What are the main findings?
Successfully established a stable, high-success-rate, and high-throughput comprehensive platform for ACC organoids culture.ACC organoids platform enables efficient screening of multiple drugs within two weeks.

Successfully established a stable, high-success-rate, and high-throughput comprehensive platform for ACC organoids culture.

ACC organoids platform enables efficient screening of multiple drugs within two weeks.

What are the implications of the main findings?
Providing an in vitro research model for personalized precision medicine in ACC, contributing to a deeper understanding of tumor biological characteristics.The rapid drug screening system holds promise as a clinical tool for medication guidance, providing a scientific basis for safer and more effective patient treatment.

Providing an in vitro research model for personalized precision medicine in ACC, contributing to a deeper understanding of tumor biological characteristics.

The rapid drug screening system holds promise as a clinical tool for medication guidance, providing a scientific basis for safer and more effective patient treatment.

Salivary adenoid cystic carcinoma (ACC) is a highly aggressive salivary gland malignancy characterized by infiltrative growth patterns that hinder complete resection. Lacking effective chemotherapy, recurrent or metastatic ACC remains clinically incurable. This research aimed to develop an efficient culture system for ACC organoids, which can preserve tumor heterogeneity and establish a reliable drug screening platform. Under our optimized culture conditions, ACC organoids grew rapidly and successfully recapitulated three characteristic histopathological patterns. Whole-genome sequencing (WGS) further confirmed they mirrored the genomic features of their parental tumors, including significantly mutated genes, non-coding regulatory region mutations, copy number variation, and minor allele frequency. RNA sequencing confirmed that ACC organoids recapitulated the MYB-NFIB fusion gene. At the protein level, these organoids contained multiple cellular components, including epithelial cells, mesenchymal cells, K7+ duct cells, a-SMA+ myoepithelial cells, K5+ basement membrane cells, and CD44+ tumor stem cells, with proper spatial distribution patterns. With an 88% success rate, the first ACC organoid platform, incorporating normal salivary gland (SG) organoids as toxicity controls, enabled high-throughput drug testing within two weeks. In conclusion, we developed an efficient culture system for ACC organoids that can preserve tumor heterogeneity and establish a reliable drug screening platform for mechanistic studies and personalized precision therapy research.

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