Causes and functional intricacies of inter- and intratumor heterogeneity of primary liver cancers.

Tumor heterogeneity is a major feature of primary liver cancers. Defined as the unique genotypic and phenotypic differences of cancer cells within a single tumor (intratumor) or amongst different patients (intertumor), tumor heterogeneity has consistently been linked to worse clinical outcomes in most, if not all, solid tumor types. In particular, liver cancer heterogeneity has been associated with altered immune infiltration, resistance to therapeutics, and worse overall patient survival. Current advancements in single-cell omic technologies have allowed for a deeper understanding and appreciation of the intricate composition and relationships between individual cells within a tumor. These observations have led to the discovery of new cell types in liver cancer, potential new mechanisms of therapy resistance and tumor progression, and new insights into the evolutionary patterns of liver cancer. To better understand the tumor biology of liver cancers and their heterogeneous features, we will begin this chapter on a brief background of liver cancer and then discuss the various etiologies of this disease and how each one can contribute to diverse genomic, transcriptomic, proteomic, and spatial architecture observations. Next, we will go into the specific causes and implications of tumor heterogeneity and end with how understanding the spatial architecture of liver tumors can provide us with new insights and ideas for tumor diversity and therapeutic development.