Related Experiment Video
Updated: Aug 6, 2026
Establishment and Culture of Patient-Derived Breast Organoids
Published on: February 17, 2023
Multi-regional Organoid Biobank Reveals FAK-ACSL1-Driven Doxorubicin-Resistance and Predictive Biomarkers in Breast
Hao Xu1,2,3,4, Zhijun Qin5, Jiapeng Yang6
1The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, P. R. China.
Abstract:
Inter-tumor and intra-tumor heterogeneity present significant challenges to achieving precise treatment in breast cancer (BC). To address this, we established a living biobank comprising 68 patient-derived organoids (PDOs) from 50 patients across various regions, accurately maintaining the histological, genomic, and transcriptomic characteristics of the original tumors. Paired profiling demonstrated high concordance in mutation burden, copy number alterations, and molecular subtypes, capturing both inter- and intra-tumor heterogeneity. Drug screening with four clinically used agents revealed pronounced response variability, enabling the development of multi-gene expression signatures predictive of drug sensitivity. ACSL1 emerged as a key mediator of Doxorubicin resistance, enriched in malignant epithelial cells exhibiting focal adhesion/MAPK pathway activation and immune-evasive features. Functional and mechanistic analyses identified focal adhesion kinase (FAK) as an upstream regulator of ACSL1, mediating resistance via ERK and STAT3 signaling. Inhibiting FAK or ACSL1 through pharmacological methods increased the sensitivity of resistant PDOs to Doxorubicin. The combined treatment was effective in decreasing tumor growth and preventing metastasis in xenograft models. Clinically, elevated ACSL1 expression correlated with advanced disease and poor survival. Collectively, these findings define BC heterogeneity, establish prognostic biomarkers, as well as uncover a means of Doxorubicin resistance that supports rational combination therapy.
Insights
Patient-derived organoids reveal breast cancer heterogeneity and drug resistance mechanisms. Targeting ACSL1 and FAK shows promise for improving Doxorubicin treatment efficacy.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Breast cancer (BC) heterogeneity complicates precise treatment strategies.
- Patient-derived organoids (PDOs) offer a model to study tumor diversity.
Purpose of the Study:
- To characterize breast cancer heterogeneity using PDOs.
- To identify predictive biomarkers for drug sensitivity and resistance.
- To uncover novel therapeutic targets for Doxorubicin resistance.
Main Methods:
- Established a biobank of 68 PDOs from 50 patients.
- Performed paired genomic and transcriptomic profiling.
- Conducted drug screening and developed gene expression signatures.
- Investigated mechanisms of Doxorubicin resistance involving ACSL1 and FAK.
- Validated findings in xenograft models and clinical data.
Main Results:
- PDOs accurately recapitulated tumor heterogeneity.
- Significant variability in drug response was observed.
- ACSL1 was identified as a mediator of Doxorubicin resistance via focal adhesion/MAPK pathways.
- FAK inhibition sensitized resistant PDOs to Doxorubicin.
- Combined FAK/ACSL1 inhibition reduced tumor growth and metastasis in vivo.
- High ACSL1 expression correlated with advanced BC and poor survival.
Conclusions:
- PDOs are valuable tools for studying breast cancer heterogeneity and drug response.
- ACSL1 and FAK are key players in Doxorubicin resistance.
- Targeting ACSL1 and FAK offers a potential strategy for overcoming Doxorubicin resistance in breast cancer.
