Targeting the Roots of Cancer Through a Deeper Understanding of Cancer Stemness

Cancer is a complex biological system that can be examined through multiple conceptual frameworks. The “Hallmarks of Cancer,” initially published by Hanahan and Weinberg in 2000 and subsequently updated in 2011, serve as a foundational model for understanding the molecular and cellular features that characterize malignancy. Most recently, in 2022, Hanahan et al. introduced “Hallmarks of Cancer: New Dimensions”, which emphasizes additional emerging hallmarks and enabling characteristics, notably those encompassed under the concept of ‘unlocking phenotypic plasticity.’

Compared to the extensive differentiation processes during organogenesis—where cells undergo significant developmental specialization—normal somatic cells are generally restricted in their capacity to differentiate, maintaining tissue organization and function. In contrast, cancer cells often acquire molecular and phenotypic alterations that confer increased plasticity, enabling them to adopt diverse cell states along a phenotypic continuum. This phenotypic plasticity facilitates non-genetic, dynamic cell state transitions that contribute to tumor heterogeneity and promote mechanisms of therapy resistance. Tumors frequently contain less differentiated, stem-like cell populations that exhibit resistance to conventional treatments and are associated with tumor relapse and metastasis.

Our research focuses on elucidating how a de-differentiated, stemness-like cellular state in cancer contributes to therapeutic resistance and disease recurrence. We utilize model systems of tumor types prevalent in Southeast Asia and Hong Kong, like hepatocellular carcinoma. Our approach integrates molecular, cellular, OMICs, and disease modeling methodologies in both basic and preclinical studies. The ultimate aim is to translate these scientific insights into improved clinical strategies for patient management and therapy.