Decoding the basis of histological variation in human cancer

Molecular abnormalities that shape human neoplasms dissociate their phenotypic landscape from that of the healthy counterpart. Through the lens of a microscope, tumour pathology optically captures such aberrations projected onto a tissue slide and has categorized human epithelial neoplasms into distinct histological subtypes based on the diverse morphogenetic and molecular programmes that they manifest. Tumour histology often reflects tumour aggressiveness, patient prognosis and therapeutic vulnerability, and thus has been used as a de facto diagnostic tool and for making clinical decisions. However, it remains elusive how the diverse histological subtypes arise and translate into pleiotropic biological phenotypes. Molecular analysis of clinical tumour tissues and their culture, including patient-derived organoids, and add-back genetic reconstruction of tumorigenic pathways using gene engineering in culture models and rodents further elucidated molecular mechanisms that underlie morphological variations. Such mechanisms include genetic mutations and epigenetic alterations in cellular identity codes that erode hard-wired morphological programmes and histologically digress tumours from the native tissues. Interestingly, tumours acquire the ability to grow independently of the niche-driven stem cell ecosystem along with these morphological alterations, providing a biological rationale for histological diversification during tumorigenesis. This Review comprehensively summarizes our current understanding of such plasticity in the histological and lineage commitment fostered cooperatively by molecular alterations and the tumour environment, and describes basic and clinical implications for future cancer therapy.