Researchers have discovered a protein system that helps explain why some colorectal cancer patients don’t respond to chemotherapy, offering hope for more effective and personalized treatments. The team found that tumors often rely on the cystine/glutamate transporter (Xc-) to survive stress and resist cell death. When this system was blocked in lab models, the cancer became more sensitive to treatment. Importantly, the scientists also identified a unique protein “signature” that could predict which patients are likely to resist standard therapies, paving the way for doctors to tailor treatments more precisely. Beyond colorectal cancer, the findings may also shed light on other cancers and even neurological conditions, making this a promising step toward smarter, more targeted medicine.

An international team of researchers has uncovered a promising new avenue for treating colorectal cancer, the world’s third leading cause of cancer-related deaths. By analyzing patient-specific genetic data, scientists identified a protein system that could predict chemotherapy resistance and open the door to more tailored, effective treatments.

The study, led by Prof. Michal Linial, Prof. Or Kakhlon and Keren Zohar of Hebrew University of Jerusalem, together with Prof. Ulf D. Kahlert and Dr. Marco Strecker of University Medicine Magdeburg, Otto-von Guericke University, published in Molecular Oncology, compared tumor and healthy tissue from 32 colorectal cancer patients. Using advanced sequencing, histology of tumor samples, and patient-derived tumor models, the team uncovered a critical role for the cystine/glutamate transporter system, known as Xc-, in driving tumor growth and treatment resistance.

A Personalized Approach to Cancer Treatment
The researchers focused on gene called SLC7A11 (xCT), which was found to be consistently overexpressed in tumor samples. When combined with another partner gene, it helps form the Xc- transporter, a mechanism cancer cells use to regulate stress and resist cell death.

By disrupting this transporter system in lab models and patient-derived organoids, the team demonstrated that blocking it could make tumors more vulnerable to treatment. The findings also revealed a unique protein “signature” on the surface of tumor cells that may serve as a biomarker to predict which patients are likely to resist conventional chemotherapy.

Implications Beyond Colon Cancer
The research highlights new opportunities to target ferroptosis - a form of programmed cell death that cancer cells often evade. Importantly, the same biological pathways also connect to processes of neuronal survival, suggesting potential relevance for other cancers and possibly neurological disorders.

“Our study shows the power of integrating patient-specific data with functional models,” said Prof. Linial. “This approach doesn’t just identify what makes each patient’s tumor unique, it shows us where the cancer is most vulnerable.”

Prof. Kahlert added: “These findings could help design new therapies that are both more effective and more personalized, offering hope for patients facing this devastating disease.”

Toward Clinical Impact

The discovery positions the Xc- transporter as a predictive therapeutic target in colorectal cancer and underscores the importance of using a careful bioinformatic analysis led by Keren Zohar. In this analysis, each tumor sample was directly compared to a normal sample from the same patient. Thus, overcoming the diversity among tumor samples. The patient-derived models were utilized to validate computational predictions. The researchers hope their work will accelerate the development of new drugs and treatment strategies aimed at improving survival and quality of life for colorectal cancer patients worldwide.