Advances in tumor subclone formation and mechanisms of growth and invasion

Abstract

Tumor subclones refer to distinct cell populations within the same tumor that possess different genetic characteristics. They play a crucial role in understanding tumor heterogeneity, evolution, and therapeutic resistance. The formation of tumor subclones is driven by several key mechanisms, including the inherent genetic instability of tumor cells, which facilitates the accumulation of novel mutations; selective pressures from the tumor microenvironment and therapeutic interventions, which promote the expansion of certain subclones; and epigenetic modifications, such as DNA methylation and histone modifications, which alter gene expression patterns. Major methodologies for studying tumor subclones include single-cell sequencing, liquid biopsy, and spatial transcriptomics, which provide insights into clonal architecture and dynamic evolution. Beyond their direct involvement in tumor growth and invasion, subclones significantly contribute to tumor heterogeneity, immune evasion, and treatment resistance. Thus, an in-depth investigation of tumor subclones not only aids in guiding personalized precision therapy, overcoming drug resistance, and identifying novel therapeutic targets, but also enhances our ability to predict recurrence and metastasis risks while elucidating the mechanisms underlying tumor heterogeneity. The integration of artificial intelligence, big data analytics, and multi-omics technologies is expected to further advance research in tumor subclones, paving the way for novel strategies in cancer diagnosis and treatment. This review aims to provide a comprehensive overview of tumor subclone formation mechanisms, evolutionary models, analytical methods, and clinical implications, offering insights into precision oncology and future translational research.

Keywords: Big data in oncology; Clonal evolution; Genomic instability; Intratumoral heterogeneity; Multi-omics integration; Phylogenetic analysis; Tumor subclones.

Fig. 1

Formation and Evolution of Tumor Subclones. This figure illustrates the formation and evolution of tumor subclones and their contribution to tumor heterogeneity. Normal cells acquire mutations and gradually develop hallmark cancer traits such as rapid proliferation, immune evasion, and angiogenesis. Truncal mutations lead to the emergence of a parental cancer cell, which undergoes clonal expansion to form the initial tumor clone. Subsequently, subclonal diversification is driven by additional genetic and epigenetic alterations, spatial constraints, and selective pressures such as therapy and immune surveillance. These processes follow a branched evolutionary model, resulting in clonal selection, extinction, and the emergence of new clones. The dynamic interplay of these factors generates functional, temporal, and spatial heterogeneity, which complicates therapeutic strategies and accelerates tumor progression