Hallmarks of an Aging and Malignant Tumor Microenvironment and the Rise of Resilient Cell Subpopulations

Intratumor heterogeneity, which includes intrinsic differences in cancer cells and morphological differences in the tissue architectures, represents a major challenge in understanding and treating cancer. Additionally, physical and molecular interactions between cancer cells and their surrounding tumor microenvironment, with its diversity in cell types and matrix mechanics, play a critical role in directing tumor growth and cancer progression. This chapter discusses how physical and molecular aspects of hallmark cancer traits and the tumor microenvironment have contributed to our understanding of cancer cell behavior. We discuss how the evolution of a malignant tumor microenvironment can protect, foster, and even prime stromal and cancer populations against future therapy-associated stress. Specifically, we highlight the development of senescent stromal populations and polyploidal giant cancer cells – resilient subpopulations contributing to chemoresistance and disease recurrence. We summarize key studies used to profile cell forces, cytoskeletal mechanics, and a number of other cell variables (i.e., morphology, migration, proliferation) that are important in cancer progression. These physical approaches are combined with molecular analysis to systematically examine tumor microenvironment conditions that control cell behavior, prime against therapeutic interventions, and contribute to the inherent heterogeneity in tumor microenvironments.