Lab-grown patient tumor miniatures offer new hope for treating esophageal cancer

Esophageal cancer remains one of the world’s deadliest cancers, ranking 7^th in incidence and 6^th in cancer-related deaths globally. In East Asia and Japan, over 90% of these cases are esophageal squamous cell carcinoma (ESCC). A reason for poor treatment outcomes is the high recurrence of ESCC, with only 55% to 63.6% of patients remaining cancer-free five years after treatment.

Given the urgent need for effective therapies targeting chemotherapy-resistant ESCC, a research team led by Professor Toshiaki Ohteki and former Associate Professor Taku Sato (currently a Professor at Nippon Medical School) from the Medical Research Laboratory at Institute of Science Tokyo (Science Tokyo), Japan, developed a patient-derived organoid library. These organoids, which are 3D miniatures of cancers grown in the lab from patient tumor samples, were used to study the mechanisms of drug resistance and screen potential therapeutic candidates.

The findings, published in Volume 8 of the journal Communications Biology on April 1, 2025, were the result of collaboration with researchers from the Department of Gastrointestinal Surgery and Department of Comprehensive Pathology at Science Tokyo, as well as Keio University and the Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital.

"Unlike artificial models that are developed by repeatedly exposing cancer cell lines to chemotherapy over time, the chemo-resistant ESCC organoids more accurately reflect the traits of the original patient tumors. Because we have established several chemo-resistant ESCC organoid lines with different oncogenic mutations, they offer a valuable tool for identifying effective drugs tailored to various forms of chemotherapy resistance,” explains Prof. Ohteki.

The research team grew organoids from tumor samples of 24 patients with ESCC with diverse backgrounds and treatment histories. These lab-grown mini-tumors closely resembled the patient’s original tumors, displaying nuclear p53 protein buildup, a common marker of TP53 mutations seen in ESCC. Each organoid also carried patient-specific mutations and showed gene activity associated with rapid cell growth and DNA replication, characteristics typical of cancer cells.

When transplanted into immunodeficient mice, the organoids developed into tumors that retained key features of the original cancers, including nuclear p53 accumulation and stratified, keratinized tissue structures.

Using the ESCC organoid library, the team tested how each organoid line responded to cisplatin and 5-fluorouracil (CF), a standard chemotherapy regimen for ESCC. While 71% of the organoids (17 lines) were sensitive to treatment, 29% (7 lines) showed resistance. Further analysis revealed increased activity in the nuclear factor erythroid 2-related factor 2 (NRF2) pathway in the resistant organoids. While the NRF2 pathway typically protects cells from oxidative stress, mutations that over activate this pathway can enhance a tumor’s antioxidant defenses, making it more resistant to chemotherapy. In all the chemo-resistant organoids, NRF2 target genes, including ALDH3A1, SPP1, and TXNRD1, were overexpressed, suggesting their potential as biomarkers for predicting chemotherapy resistance.

“About 28% of patients with ESCC do not respond well to neoadjuvant chemotherapy. Therefore, identifying biomarkers that can predict which tumors are resistant to this treatment is crucial for ensuring patients get the most appropriate and effective care early on,” says Prof. Sato.

The organoid model also proved valuable for evaluating new drug candidates. Notably, the team found that fedratinib was more effective than standard CF drugs at inhibiting the growth of chemo-resistant ESCC organoids. Interestingly, fedratinib's effectiveness was not dependent on the NRF2 pathway. Further analysis suggested that its anti-tumor effect was linked to inhibition of BRD4, a protein involved in cancer cell growth.

These findings highlight the significant potential of the organoid model for future research, which could lead to the development of therapies specifically targeting chemotherapy-resistant tumors, offering hope for patients suffering from this prevalent and deadly disease.

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About Institute of Science Tokyo (Science Tokyo)
Institute of Science Tokyo (Science Tokyo) was established on October 1, 2024, following the merger between Tokyo Medical and Dental University (TMDU) and Tokyo Institute of Technology (Tokyo Tech), with the mission of “Advancing science and human wellbeing to create value for and with society.”