Controversies around epithelial-mesenchymal plasticity in cancer metastasis

Abstract

Experimental evidence accumulated over decades has implicated epithelial-mesenchymal plasticity (EMP), which collectively encompasses epithelial-mesenchymal transition and the reverse process of mesenchymal-epithelial transition, in tumour metastasis, cancer stem cell generation and maintenance, and therapeutic resistance. However, the dynamic nature of EMP processes, the apparent need to reverse mesenchymal changes for the development of macrometastases and the likelihood that only minor cancer cell subpopulations exhibit EMP at any one time have made such evidence difficult to accrue in the clinical setting. In this Perspectives article, we outline the existing preclinical and clinical evidence for EMP and reflect on recent controversies, including the failure of initial lineage-tracing experiments to confirm a major role for EMP in dissemination, and discuss accumulating data suggesting that epithelial features and/or a hybrid epithelial-mesenchymal phenotype are important in metastasis. We also highlight strategies to address the complexities of therapeutically targeting the EMP process that give consideration to its spatially and temporally divergent roles in metastasis, with the view that this will yield a potent and broad class of therapeutic agents.

Fig. 1 |. Types of EMP stimuli.

Many categories of factors are known to induce epithelial-mesenchymal transition (EMT), the inhibition or removal of which might promote the reverse process of mesenchymal-epithelial transition (MET). Microenvironmental cells (for example, tumour-associated macrophages, hypoxic adipocytes and other inflammatory cells) produce EMT-promoting factors such as transforming growth factor-β (TGFβ), epidermal growth factor (EGF), fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), tumour necrosis factor, IL-6 (REF.) and leptin^,. Through activation of the nuclear factor-κB (NF-κB) pathway, these cells invoke crosstalk with EMT-activating transcription factors^,. Alterations of the metabolic microenvironment induced by rapid primary tumour growth might also induce EMT^–, and hypoxia, through the action of hypoxia-inducible factor 1α (HIF1α), can directly drive the expression of EMT-activating transcription factors in various tumour types^,,. Matrix stiffness has also been shown to stimulate EMT^,,. Therapeutic agents have primarily been shown to promote EMT in association with drug resistance^–,,,–, although some are associated with MET, and these cause significant improvements in disease-free survival and overall survival. Developmental pathways, which might be activated by genomic and/or epigenomic regulators, have also been implicated in epithelial-mesenchymal plasticity (EMP)^,. ECM, extracellular matrix.

Fig. 2 |. Therapy-induced EMT and potential EMT-suppressing regimens.

Epithelial-mesenchymal transition (EMT) induced by a spectrum of therapeutic agents and modalities has consequences for treatment resistance and/or metastasis across many cancer types. Potential mechanisms through which EMT might contribute to therapeutic resistance include reducing the sensitivity to proapoptotic signals (reviewed in REF.), acquisition of stemness features^–, stimulation of angiogenesis, upregulating expression of immune checkpoint molecules and increasing immune suppression by altering the balance of infiltrating immune cells^,, reducing DNA damage in concert with enhancing DNA repair^,, and upregulating expression of export pumps that actively eliminate cytotoxic drugs from cells^–. Furthermore, cells undergoing therapy-induced EMT might proliferate at decreased rates and, therefore, have decreased sensitivity to chemotherapeutic agents^,,, and migration of cancer cells to a microenvironment that is poorly accessible to drugs (for example, through the blood-brain barrier) might reduce the impact of therapeutic interventions. For example, in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, continued treatment with HER-targeted therapy (for example, trastuzumab) can trigger EMT and relapse can occur in the brain alone despite an ongoing good response elsewhere in the body. Treatment with existing or novel therapies (for example, eribulin or vinca alkaloids)^, might minimize or revert EMT-associated features and, therefore, reduce the emergence of therapeutic resistance. CRC, colorectal cancer; EMT-TF, EMT-activating transcription factor; HCC, hepatocellular carcinoma; miRNA, microRNA; NSCLC, non-small-cell lung cancer; TGFβ, transforming growth factor-β.

Fig. 3 |. Therapeutic opportunities to address EMP.

The various states produced during epitheLial— mesenchymal plasticity (EMP) provide a number of opportunities to influence cancer progression via different strategies. The supporting rationale for this concept is the notion that targeting or preventing epithelial-mesenchymal transition (EMT) to sustain epithelial differentiation or selectively targeting the mesenchymal state by inhibiting EMT-driving targets might be most effective as part of adjuvant therapy for early-stage cancers, where the invasive outgrowth of cells from established deposits as well as quiescent, stem-like, mesenchymally shifted cells that have disseminated could be addressed therapeutically. Late-stage bulky metastases, for which we have very limited effective treatment options, might respond best to therapies that reverse or prevent mesenchymal-epithelial transition (MET) and drive re-epithelial differentiation or selectively target the uniquely EMP-marked epithelial tumour cells that emerge following the EMT-MET cycle process. Further options across the treatment continuum might be to develop therapies that specifically target the unique aspects of the hybrid epithelial-mesenchymal phenotype or fix cells in the mesenchymal state to deprive cancers of the progression mechanisms associated with plasticity. EMT-TF, EMT-activating transcription factor; miRNA, microRNA.