Modeling Tumor Invasion with Spheroids Embedded in Extracellular Matrix

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Over the past decade, much experimental work has focused on how stiffening and fiber alignment in the tissue around a tumor can transform the carcinoma into a more aggressive and invasive phenotype. On the theory side, there has been recent progress on modeling strain-stiffening transitions in fiber networks, as well as modeling single-cell migration through fiber networks. However, cellular-based models have yet to describe how large collections of cells interact with surrounding tissue, and therefore cannot predict observations such as cellular streams that leave a tumor collectively, for instance. One possible reason for this surprising theoretical gap is that modeling cell-ECM interactions requires a framework that simultaneously describes cellularized and acellularized tissues as well as a (possibly convoluted) interface between them, with a minimal number of directly observable parameters, such as cell shape and fiber network microarchitecture. New experimental techniques will allow the PIs to perform measurements that can not only be directly tested against the modeling but will help guide the modeling as well. In the clinical treatment of cancers like carcinomas, it is difficult to identify biomarkers that correctly predict the aggressiveness of a tumor in an individual patient. It is also difficult to quantify how the microenvironment of a tumor might alter the prognosis for a particular patient. The research proposed here will address these two problems using ideas that are complementary to the ones typically being explored in cancer biology labs, by identifying how experimentally-accessible metrics correlate with tumor invasiveness and perhaps even patient outcomes. The PIs suggest that structural biomarkers such as cell shape and fiber alignment may work together to specify tumor invasiveness. To broaden the participation in the growing interdisciplinary fields of tissue mechanics and active matter, the PIs will establish an inter-departmental and inter-university soft matter-biology journal club and will devise a short course on “the soft matter physics of cancer” to disseminate at venues such as the Boulder school for condensed matter and other summer schools. These endeavors should help generate interest among a new generation in important problems at the intersection of soft matter and biology.The PIs will use theoretical and experimental tools to quantify the interactions between a multicellular tumor spheroid and its extracellular matrix (ECM) environment. Their hypothesis is that bulk rheology and interfacial energies place strong constraints on how the spheroid and ECM interact to stabilize or destabilize the tumor boundary and, thereby, govern tumor invasiveness. Their prior theoretical work demonstrates that both vertex models for dense, cellularized tumors and fiber network models for the acellular extracellular matrix (ECM) exhibit similar rigidity transitions driving their respective rheologies. Additional theoretical work has carefully characterized the surprising dynamics of interfaces between two different tissue types in these models. Finally, they have developed a powerful experimental technique to probe the mechanical interactions between single breast tumor cells and extracellular matrices. This technique will now be applied to multicellular tumor spheroids. Therefore, the PIs are well-poised to develop testable predictions for tumor invasion in this model system. They first will theoretically and experimentally study how the rheology of the tumor spheroid, coupled to the ECM, via a mechanosensitive interfacial energy modulates the competition between cell-cell adhesion and cell- ECM adhesion to deform a stable tumor-ECM boundary. They will then investigate how cell growth, relevant at longer time scales, affects this competition to lead to deformable and propagating, stable tumor-ECM boundaries. Finally, they will explore under what conditions the spheroid-ECM boundary ultimately destabilizes at the individual and/or multicellular scale to lead to invasion of the surrounding tissue.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.