Congratulations to Dr. Meghan Ferrall-Fairbanks on co-authoring the article Modeling collective cell behavior in cancer: perspectives from an interdisciplinary conversation, in Cell Systems.
A group of researchers from diverse biological and quantitative fields recently gathered for a 5-day innovation lab facilitated by the National Cancer Institute titled “Modeling Emergent Cellular Behavior in Cancer” (February 25–26 and March 1–2, 5, 2021) to consider the processes by which the behavior of individual cells and their interactions generate the collective behavior of cancerous tissues, and to draw lessons from other scientific disciplines that have met similar challenges. Here, we summarize the major themes of this conversation.
Efforts to understand cancer have traditionally examined how a single cell acquires, through a series of stepwise mutations, the ability to survive, grow, and move when it otherwise should not. The focus on individual cells has led to important discoveries about the functions of oncogenes and tumor suppressors, cell-cycle checkpoints, control of cell growth, repair of DNA damage, and mechanisms of cell death; however, it has fallen far short of illuminating a more integrated and systemic understanding of cancer development.
More recently, there has been a shift away from the “one rogue cell” view of cancer, with more and more cancer biologists and engineers beginning to view this disease as a complex system in which the acquired abilities of cancer cells are critically tied to their interactions with other cell types, both mutated and not, and firmly rooted in cellular behaviors beyond cell survival, growth, division, and movement.
Dr. Ferrall-Fairbanks’ perspective:
New engineered systems enable researchers to monitor and induce dynamic cell-cell interactions in complex environments in mouse. Microphysiological systems provide a reductionist approach for building mini cellular “ecosystems” that are more amenable to imaging, molecular analysis, and perturbation. Ongoing development and adoption of tools such as this is required to test and refine conceptual and computational models of multicellular processes in cancer.
Collective behavior in cancer emerges through the repurposing of the same basic biomolecular components used to build or maintain the normal tissue from which they are derived. For example, cell-cell interactions that are critical during normal pre- and post-natal development are typically suppressed in most adult tissues but can become reactivated in tumors. One set of interactions act to suppress the immune microenvironment around the placenta during fetal development and are critical to prevent rejection of the fetus by the maternal immune system. Near parturition this process is reversed by proinflammatory factors, leading to physiologic rejection of the developed fetus. This natural immune suppression during pregnancy results in relief of the symptoms of autoimmune disorders in pregnant women. Conversely, tumors tolerated by pregnant mice are rejected after parturition. The reversible nature of maternal-fetal tolerance can help us understand how to harness the immune system to combat cancer.
Identifying cancer cell behaviors and enumerating their genetic and molecular underpinnings has explained much about cancer progression; however, key steps in the process have resisted explanation, limiting our understanding of initiation, metastasis, recurrence, and response to treatment. Studying cancer as a multicellular process involving diverse interaction and feedback mechanisms at the tissue level will be critical for advancing the field. The team proposes that because collective behaviors play essential roles in cancer progression and resistance to treatment, untangling the cellular interaction network that regulates collective behaviors will provide new strategies for slowing, halting, reversing, and even preventing cancer.