The Burden of Liver Cancer in Singapore and NUS's Pivotal Role

Liver cancer remains one of the most pressing health challenges in Singapore, ranking as the third leading cause of cancer death among men and fifth among women. Hepatocellular carcinoma (HCC), the predominant form, and intrahepatic cholangiocarcinoma (ICC), a rarer but highly aggressive subtype, contribute significantly to this burden. Recent data from the Singapore Cancer Registry indicates a 21% decline in cancer death rates since 2012, thanks to advances in screening, treatment, and research led by institutions like the National University of Singapore (NUS).

NUS Medicine, through its Centre for Cancer Research (N2CR), is at the forefront of dissecting the complexities of liver cancer. Researchers at NUS have been instrumental in identifying molecular drivers that distinguish aggressive subtypes, paving the way for precision medicine. This work not only enhances our understanding but also positions Singapore as a hub for oncology research in Asia.

Understanding Intrahepatic Cholangiocarcinoma: The Aggressive Liver Cancer Subtype

Intrahepatic cholangiocarcinoma (ICC) originates in the bile ducts within the liver and accounts for about 10-15% of primary liver cancers. Unlike HCC, which arises from hepatocytes, ICC is characterized by rapid growth, early metastasis, and poor prognosis, with five-year survival rates below 30%. Its aggressiveness stems from tumor heterogeneity, where diverse cell populations coexist, driving resistance to standard therapies like chemotherapy and targeted drugs.

NUS researchers have zeroed in on ICC as a critical area, revealing how certain molecular signatures amplify its malignancy. This subtype poses unique challenges due to its biliary origin, often linked to chronic liver inflammation, viral hepatitis, or genetic predispositions prevalent in Asian populations.

NUS Breakthrough: Classifying ICC Tumours and Discovering the SPINK1-High Subgroup

In a landmark study from NUS's N2CR, led by Associate Professor Gautam Sethi, advanced laboratory techniques including single-cell RNA sequencing and proteomics classified ICC tumours into distinct molecular groups. The standout discovery was the SPINK1-high subgroup, marked by elevated levels of Serine Protease Inhibitor Kazal-type 1 (SPINK1), a protein previously associated with pancreatic and prostate cancers.

SPINK1-high ICC tumours exhibited heightened invasiveness, proliferation, and immune evasion, correlating with worse patient outcomes. This aggressive liver cancer subtype demonstrated upregulated pathways for epithelial-mesenchymal transition (EMT), a process where cancer cells gain migratory abilities, facilitating metastasis to distant organs like lungs and peritoneum.

The research utilized patient-derived organoids and mouse models to validate these findings, showing that SPINK1 drives tumor plasticity, allowing cells to switch between states resistant to treatment.

Deciphering the Mechanisms: How SPINK1 Fuels Aggressiveness

SPINK1 overexpression in the aggressive liver cancer subtype promotes a pro-tumorigenic microenvironment. It activates signaling cascades like NF-κB and STAT3, fostering inflammation and angiogenesis. Step-by-step, SPINK1 binds to receptors on cancer-associated fibroblasts and macrophages, recruiting them to remodel the extracellular matrix, enabling invasion.

In Singapore's context, where chronic hepatitis B affects 3.5% of the population, this subtype exacerbates risks. NUS studies link SPINK1 to viral integrations and copy number variations observed in regional cohorts.

• Increased tumor cell survival under stress
• Enhanced metastasis potential
• Resistance to sorafenib and immunotherapy

Research Methods: From Multi-Omics to Functional Validation

NUS researchers employed a multi-omics approach: genomic sequencing for mutations, transcriptomics for gene expression, and proteomics for protein levels across 100+ ICC samples. Machine learning clustered tumours into subtypes, with SPINK1 emerging as a top biomarker.

Functional assays confirmed causality: CRISPR knockout of SPINK1 reduced tumor growth by 60% in xenografts. This rigorous methodology, combining computational biology and wet-lab experiments, exemplifies NUS's translational research prowess.

Clinical Implications: Stratifying Patients and New Therapies

The SPINK1 biomarker enables risk stratification: high levels predict recurrence within 12 months post-resection. In Singapore clinics, integrating SPINK1 testing could guide adjuvant therapies. Potential treatments include SPINK1 inhibitors, already in trials for other cancers, and combination with PD-1 blockers to overcome immune suppression.SPINK1-CCL20 axis study

This could improve survival from 20% to over 40% for high-risk patients, reducing healthcare burden estimated at S$500 million annually.

Singapore's Liver Cancer Landscape: Statistics and Trends

In 2023, Singapore recorded 1,200 new liver cancer cases, with projections to 1,500 by 2030 due to aging and NAFLD rise. ICC comprises 15%, disproportionately aggressive. NUS-led PLANet consortium analyzes Asia-Pacific cohorts, revealing ethnic variations—Chinese patients show higher SPINK1 prevalence.

• Age-adjusted incidence: 15.7 per 100,000
• Male:female ratio 4:1
• 5-year survival: 25% overall, 10% for metastatic

NUS's Ecosystem for Oncology Innovation

NUS fosters interdisciplinary research via N2CR, partnering with A*STAR GIS and Duke-NUS. Facilities like the Organoid Day 2026 highlight precision oncology. Students and postdocs gain hands-on experience, contributing to global outputs—NUS ranks top in Asia for clinical medicine.Explore higher ed jobs at NUS

This environment attracts top talent, driving discoveries like the 'bad apple' effect in HCC heterogeneity.

Challenges and Solutions in Targeting Aggressive Subtypes

Challenges include tumor heterogeneity and drug resistance. NUS addresses via AI-driven predictions and nanomedicines. For instance, recent work on fatty liver precursors prevents progression to ICC/HCC.

Solutions:

• Multi-regional biopsies
• Personalized organoid screening
• Combo therapies

Future Outlook: Precision Medicine at NUS

Upcoming NUS trials test SPINK1 blockers, with PLANet 2.0 expanding spatial omics. By 2030, expect subtype-specific therapies boosting survival 50%. Singapore's investment in NRF grants underscores commitment.NCCS precision oncology

Photo by Markus Winkler on Unsplash

Career Opportunities in Singapore's Cancer Research Landscape

NUS offers PhD programs, postdoc positions, and faculty roles in oncology. With rising demand for experts in genomics and immunotherapy, graduates secure roles at higher-ed faculty positions or industry. Platforms like Rate My Professor highlight mentors like A/Prof Sethi.

Check higher ed career advice for tips on entering this field.