SINGAPORE: Researchers from the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine) have uncovered a key molecular mechanism that could revolutionize the treatment of colorectal cancer (CRC).
The discovery, published in Nature Communications, sheds light on the role of Dual-Specificity Phosphatase 6 (DUSP6), a molecule that has been found to play a significant part in the aggressive growth of CRC.
Colorectal cancer, one of the most common cancers in Singapore, with approximately 2,540 new cases annually, remains a leading cause of cancer-related mortality in the country. The disease, which begins in the colon or rectum, often starts as benign polyps that can develop into cancerous growths if left untreated.
Globally, CRC ranks as the third most common cancer, responsible for about 10% of all cancer diagnoses, according to the World Health Organization (WHO). Despite advances in treatment, CRC remains a challenge due to the high rates of recurrence and the development of drug resistance.
The NUS study reveals that elevated levels of DUSP6 are associated with increased CRC cell proliferation. Cells with higher DUSP6 levels proliferated nearly 40% faster than those with lower levels. Additionally, patients with CRC exhibiting high DUSP6 levels had poorer prognoses and shorter survival rates, underscoring the molecule’s role as a potential therapeutic target.
DUSP6 is a phosphatase protein that regulates the ERK1/2 MAPK signalling pathway, a key pathway responsible for cell growth, survival, and repair. While DUSP6 typically acts as a tumour suppressor in some cancers by deactivating ERK1/2 to prevent unchecked cell growth, it has the opposite effect in CRC, promoting tumour progression.
The study’s lead researcher, Associate Professor Zhang Yongliang from the Department of Microbiology & Immunology at NUS Medicine, explained that DUSP6 facilitates faster cancer cell growth and spread in CRC by preventing the breakdown of Notch1, a protein crucial for cellular communication and growth regulation.
Notch1, when overactive, can drive tumour growth and contribute to cancer survival. Normally, Notch1 is marked for destruction after its activity is triggered, but DUSP6 inhibits this process, allowing Notch1 to remain active longer than necessary, promoting uncontrolled cell growth. The result is a faster-spreading cancer and worse survival outcomes for CRC patients.
Associate Professor Veronique Angeli, Director of the Immunology Translational Research Programme at NUS Medicine, emphasized that DUSP6’s role in protecting Notch1 is pivotal in CRC. By allowing Notch1 to stay active, DUSP6 accelerates the progression of the cancer, making it a prime candidate for targeted therapy development.
The research team’s experiments on laboratory models show that blocking DUSP6 can significantly slow tumour growth, offering a potential new approach to treating CRC. This discovery also suggests that DUSP6 levels could serve as a biomarker to predict the aggressiveness of CRC, aiding in the development of more personalized treatment strategies.
Looking ahead, the team aims to further explore the role of DUSP6 in CRC pathogenesis and develop targeted therapies that can block its activity, offering new hope for patients facing this challenging disease. This breakthrough not only advances understanding of CRC but also holds promise for improving survival rates and treatment outcomes.