Figure 3.

Three-dimensional models employed to study different cellular events during tumor progression and dissemination

(A) Immune cell recruitment. Microfluidic device with two adjacent gel channels (red) flanked by media channels (blue) is used for the study of macrophage migration in the presence of tumor cells. Tumor cells and macrophages are suspended in collagen I in separate gel channels. Single-cell analysis of macrophage migration demonstrates that macrophages have higher speed and directedness when co-cultured with tumor cells compared with controls.

(B) Tumor cell dissemination. A device similar to that in (A) was used to study epithelial-mesenchymal transition (EMT). Tumor spheroids are suspended in gel, and macrophages are either suspended together in the same or an adjacent but different channel than the tumor spheroid. After 36 h, tumor spheroids cultured with M2a macrophages, but no other sub-type, dispersed more readily when in contact with the tumor as opposed to separated. Scale bars: 100 μm.

(C) Tumor cell invasion at the metastatic site. First, monocytes are introduced into the endothelialized center channel and allowed to extravasate. Two days later, tumor cells are introduced into the same channel. Monocyte migration created microtracks that facilitated tumor cell invasion into the ECM. Scale bars:10 µm.

(D) Angiogenesis. Open-top, stackable, microfluidic devices demonstrate different effects of tumor cell phenotypes on angiogenesis through induction of TAMs. This study showed that different tumor prostate cancer phenotypes resulted in different vessel morphologies through modulation of TAM phenotypes. Scale bars: 150 μm.

(E) Cytotoxicity. Effects of antibody drugs on tumor cell killing by NK cells is recapitulated by a microfluidic platform that has tumor cells and NK cells in gel suspension, and drugs diffuse from the media channel. This study reports the capability of NK cells to induce tumor cell apoptosis.

(F) Immunosuppression. Effector T cell suppression by monocytic cells are modeled by capturing tumor-killing efficacy within a microfluidic device. Tumor cells and monocytes are suspended in the gel channel, whereas effector T cells are introduced into the media channel. T cells migrate then to the gel channel, toward tumor cells and kill them. However, the presence of monocytic cells in the gel impeded the killing efficacy. Using check point blockade targeting PD-L1/PD-1 signaling, T cell cytotoxicity is restored.

Figures are adapted from the following publications: (A–F) panels are respectively from Lee et al., 2020; Bai et al., 2015; Kim et al., 2019a; Yu et al., 2019; Ayuso et al., 2019; Lee et al., 2018):