Interplay between tumor microenvironment and partial EMT as the driver of tumor progression

Abstract

Epithelial-to-mesenchymal transition (EMT), an evolutionary conserved phenomenon, has been extensively studied to address the unresolved variable treatment response across therapeutic regimes in cancer subtypes. EMT has long been envisaged to regulate tumor invasion, migration, and therapeutic resistance during tumorigenesis. However, recently it has been highlighted that EMT involves an intermediate partial EMT (pEMT) phenotype, defined by incomplete loss of epithelial markers and incomplete gain of mesenchymal markers. It has been further emphasized that pEMT transition involves a spectrum of intermediate hybrid states on either side of pEMT spectrum. Emerging evidence underlines bi-directional crosstalk between tumor cells and surrounding microenvironment in acquisition of pEMT phenotype. Although much work is still ongoing to gain mechanistic insights into regulation of pEMT phenotype, it is evident that pEMT plays a critical role in tumor aggressiveness, invasion, migration, and metastasis along with therapeutic resistance. In this review, we focus on important role of tumor-intrinsic factors and tumor microenvironment in driving pEMT and emphasize that engineered controlled microenvironments are instrumental to provide mechanistic insights into pEMT biology. We also discuss the significance of pEMT in regulating hallmarks of tumor progression i.e. cell cycle regulation, collective migration, and therapeutic resistance. Although constantly evolving, current progress and momentum in the pEMT field holds promise to unravel new therapeutic targets to halt tumor progression at early stages as well as tackle the complex therapeutic resistance observed across many cancer types.

Keywords: bioengineering; cancer; functional aspects of cell biology; tissue engineering.

Graphical abstract

Figure 1

Partial EMT (pEMT) phenotype involves a spectrum of changes between epithelial and mesenchymal phenotypes The tumor cells expressing pEMT phenotype interact with surrounding extracellular matrix, which induces tumor heterogeneity. pEMT also regulates key processes in tumor progression: cell-cycle regulation, collective migration, metastasis, and therapeutic resistance.

Figure 2

Three-dimensional (3D) microtumor models to study tumor-intrinsic hypoxia-driven migration (A–F) (A) Size-controlled hydrogel microwell arrays (150 and 600 μm) used to generate the microtumors. (B) Photomicrographs show size-controlled 150 μm microtumors and 600 μm microtumors on day 1. (C) Hypoxia signature in large hypoxic 600 μm microtumors. (D) Hypoxia is absent in non-migrating 150 μm microtumors from day 1 to day 6. In large 600 μm microtumors, hypoxia is observed from day 1 to day 6 in the migrating 600 μm microtumors. Scale bars: 300 μm (top panel) and 250 μm (bottom panel). (E) Large microtumors show significant increase in sub G0/G1 phase and decrease in G0/G1 phase with no differences in S and G2/M phase compared with 2D and small microtumors (reproduced from Singh et al., 2018a). (F) Immunofluorescence images of microtumors showed uniform E-cad (green) staining in large microtumors, whereas VIM (red) was expressed only at the periphery in large microtumors.

Figure 3

Three-dimensional (3D) bioengineering platforms used to study partial EMT phenotype (A) 96-well low attachment plate. (B) Hanging drop spheroid culture method, adapted with permission Kuo et al. (2017). (C) Soft-agar-coated spheroid model, adapted with permission from Chaicharoenaudomrung et al. (2019). (D) Collagen matrix for studying microenvironment interactions with tumor cells, adapted with permission from Kasai et al., (2017). (E) Microfluidic platform, reproduced from Kuo et al. (2014) with permission from The Royal Society of Chemistry. (F) Breast tumor cells-adipocytes co-culture model, adapted with permission from cross-reference to Debnath et al. (2003).