TY - JOUR
T1 - Integrated in silico and 3D in vitro model of macrophage migration in response to physical and chemical factors in the tumor microenvironment
AU - Lee, Sharon Wei Ling
AU - Seager, R J
AU - Litvak, Felix
AU - Spill, Fabian
AU - Sieow, Je Lin
AU - Leong, Penny Hweixian
AU - Kumar, Dillip
AU - Tan, Alrina Shin Min
AU - Wong, Siew Cheng
AU - Adriani, Giulia
AU - Zaman, Muhammad Hamid
AU - Kamm, And Roger D
PY - 2020/4/6
Y1 - 2020/4/6
N2 - 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.
AB - 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.
KW - 3D cell migration
KW - cell signaling analysis
KW - interstitial flow
KW - macrophages
KW - microf luidic cancer models
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85083910251&partnerID=8YFLogxK
U2 - 10.1093/intbio/zyaa007
DO - 10.1093/intbio/zyaa007
M3 - Article
C2 - 32248236
SN - 1757-9694
VL - 12
SP - 90
EP - 108
JO - Integrative Biology
JF - Integrative Biology
IS - 4
M1 - zyaa007
ER -