Leader, follower, and cheater in collective cancer invasion

A major reason for the failure of cancer treatment and disease progression is the heterogeneous composition of tumor cells at the genetic, epigenetic, and phenotypic levels. Despite extensive efforts to characterize the makeup of individual cells, there is still much to be learned about the interactions between heterogeneous cancer cells and between cancer cells and the microenvironment in the context of cancer invasion. Clinical studies and in vivo models have shown that cancer invasion predominantly occurs through collective invasion packs, which invade more aggressively and result in worse outcomes. In vitro experiments on non-small cell lung cancer spheroids have demonstrated that the invasion packs consist of leaders and followers who engage in mutualistic social interactions during collective invasion. Many fundamental questions remain unanswered: What is the division of labor within the heterogeneous invasion pack? How does the leader phenotype emerge? Are the phenotypes plastic? What’s the role of the individual “cheaters”? How does the invasion pack interact with the stroma? Can the social interaction network be exploited to devise novel treatment strategies? I will discuss recent modeling efforts to address these questions and hope to convince you that identifying and perturbing the “weak links” within the social interaction network can disrupt collective invasion and potentially prevent the malignant progression of cancer.