Abstract 3779: Self-guided migration of cancer epithelial cells in confined environment.

Abstract

Abstract Cancer epithelial cells often migrate away from the primary tumor to invade into the surrounding tissues. Their migration is commonly assumed to be guided by pre-existent spatial gradients of chemokines and growth factors in the target tissues. Blocking the migration of cancer cells in these guiding gradients could help reduce cancer ability to invade and metastasize. However, identifying and measuring the cancer cell guiding gradients in vivo is extremely difficult due to technological limitations and substantial complexity of the biochemical environment around tumors. To this end, in vitro systems have the advantage of better control over the biochemical conditions of invasion. Unexpectedly, using a novel microscale in vitro assay, we observed that the guided migration of cancer cells from various cell lines is possible even in the absence of pre-existent chemical gradients. We discovered that single cancer cells can exit along the shortest path from microscopic mazes that are uniformly pre-filled with standard cell culture media. Up to 80% of the single cancer cells entering the mazes can exit in less than 24 hours, two orders of magnitude more cells than expected from random migration in the maze (chemokinesis) or haptotactic guidance by the walls of the maze. These unexpected results are highly suggestive for a novel, self-guidance strategy during which cancer cells generate their own guiding cues. We confirmed that the self-guidance strategy is independent from cytokine/chemokine signaling and could be perturbed by removing EGF from the media or by inhibiting signaling through EGF-receptors. Interestingly, only the ability to steer towards the exit but not the speed of migration is perturbed by the interference with EGF signaling. Furthermore, using biophysical models and quantitative microfluidic experiments, we determined that the self-guidance strategy depends on the balance between three simultaneous processes: EGF uptake by the cells, restricted diffusion of EGF in the microstructured environment, and cell chemotaxis toward the EGF gradients. Three major implications of this self-guiding strategy are emerging. (1) Cancer cell do not require pre-existing chemical gradients for guidance and thus cancer migration is not bound by the spatial limits of any gradient. (2) By simultaneously producing the gradients and responding to them, cancer cells can lock themselves into a self reinforcing loop and persistent migratory phenotype from which they cannot escape. (3) The self-guidance strategy can take place with cancer cells from human tumors, supporting the relevance of our findings to human disease. Overall, our findings suggest that new strategies are needed for delaying cancer cell invasion and stopping cancer metastasis. Citation Format: Daniel Irimia. Self-guided migration of cancer epithelial cells in confined environment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3779. doi:10.1158/1538-7445.AM2013-3779