An initial step in solid tumor metastasis involves the migration of tumor cells through extracellular matrix. Several cancer cell migration strategies exist in vivo, and the local properties of collagen fibers are implicated in modulating migration behaviors. Yet, individual tumor cells also display heterogeneity in their intrinsic ability to migrate and metastasize. It remains unclear to what extent intrinsic and extrinsic heterogeneity contribute to the emergence of distinct migration phenotypes and whether certain migration phenotypes contribute more to metastasis than others. To study this, we generated 3D collagen matrices of varying densities and monitored single cancer cell migration in these matrices with time-lapse microscopy. We observed a collagen density threshold at 2.5mg/ml, above which 86% of MDA-MB-231 breast cancer cells transition from single mesenchymal migration to collective cell migration, with a 50% increase in persistence after cell division. After seven days, these collectively migrating cells created networks coated with basement membrane molecules resembling a clinical phenotype known as vascular mimicry (VM).The remaining 14% of cells migrated randomly and eventually formed spheroids. HT-1080 fibrosarcoma cells also responded similarly, migrating persistently and forming cellular networks. Next we sought to identify the physical feature of high-density collagen driving VM. Neither hypoxia or matrix stiffness was sufficient to induce VM. However, PEG-induced matrix confinement triggered VM network formation. RNA sequencing revealed collectively migrating cells up-regulated a conserved transcriptional program significantly enriched for annotations of vascular development and motility regulation processes. This gene module predicted survival in human tumor transcriptome datasets. Our results suggest that the VM phenotype arises in a subpopulation of cells from a conserved transcriptional and migratory response to confinement in 3D collagen.

Note: This abstract was not presented at the meeting.

Citation Format: Daniel Ortiz, Brian Tsui, Tyler Goshia, Colleen Ricker, Hannah Carter, Stephanie I. Fraley. 3D matrix confinement triggers vascular mimicry through a conserved migratory and transcriptional response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1888. doi:10.1158/1538-7445.AM2017-1888