The Genetic and Mechanical Origins of Tumor Heterogeneity

Abstract

Most of the deaths from cancer are due to metastasis from primary tumor sites to other sites in the body. Heterogeneity in tumors is associated with increased metastasis and a reduction in patient survival rates. Finding ways to better understand the heterogeneity of cancer will greatly help patients diagnosed with this disease. Cancer is often heterogeneous in gene expression and mechanical features. Genetic mutations are rare in cells; however, as cells replicate and duplicate their DNA, mutations can continuously stack on. Cancer cells have rapid replication, so genetic mutations become more common. Spatial transcriptomics, which combines spatial locations and RNA sequencing, can be an effective method at measuring the genetic heterogeneity of tissue. We have found that genetic subclones, biomarkers, and heterogeneity of biological processes can all be identified and better understood using spatial transcriptomics. The tumor microenvironment frequently experiences an upregulation of tissue stiffness in a heterogeneous manner. This can cause unique behavior, including irregular angiogenesis. Irregular angiogenesis can affect the ability of the body to deliver nutrients and clear waste, disrupting the ability of the immune system and further promoting genetic mutations and tissue stiffening. Angiogenesis is mediated by endothelial cells. Using traction force microscopy and the PercevalHR probe, we have found that endothelial cells have higher traction forces and a biphasic trend of metabolism on stiffer substrates. This cellular behavior may lead to the increased likelihood of irregular angiogenesis in tumors.