Integrated in silico and 3D in vitro model of macrophage migration in response to physical and chemical factors in the tumor microenvironment

Research output: Contribution to journalArticle

Authors

  • Sharon Wei Ling Lee
  • R J Seager
  • Felix Litvak
  • Je Lin Sieow
  • Penny Hweixian Leong
  • Dillip Kumar
  • Alrina Shin Min Tan
  • Siew Cheng Wong
  • Giulia Adriani
  • Muhammad Hamid Zaman
  • And Roger D Kamm

Colleges, School and Institutes

Abstract

Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and macrophages to study how IF affects macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased macrophage migration directedness and speed. Interestingly, there was no additive effect on macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of tumor-associated macrophage-based immunotherapeutic strategies.

Details

Original languageEnglish
Article numberzyaa007
Pages (from-to)90-108
Number of pages19
JournalIntegrative Biology
Volume12
Issue number4
Publication statusPublished - 6 Apr 2020

Keywords

  • macrophages, interstitial flow, tumor microenvironment, microf luidic cancer models, 3D cell migration, cell signaling analysis