Abstract
Simple SummaryCell developmental programs used in wound healing and development such as the epithelial-to-mesenchymal transition (EMT) are frequently coopted by solid tumors to increase motility, plasticity, and invasive characteristics which promote metastasis. Identifying and quantifying the presence and extent of these programs can help to aid in patient prognosis and dictate therapeutic decision making. Here, we review the methods and findings to detect and quantify these cellular transitions in both laboratory and clinical settings.The epithelial-to-mesenchymal transition (EMT) and its reversal, the mesenchymal-to-epithelial transition (MET) are critical components of the metastatic cascade in breast cancer and many other solid tumor types. Recent work has uncovered the presence of a variety of states encompassed within the EMT spectrum, each of which may play unique roles or work collectively to impact tumor progression. However, defining EMT status is not routinely carried out to determine patient prognosis or dictate therapeutic decision-making in the clinic. Identifying and quantifying the presence of various EMT states within a tumor is a critical first step to scoring patient tumors to aid in determining prognosis. Here, we review the major strides taken towards translating our understanding of EMT biology from bench to bedside. We review previously used approaches including basic immunofluorescence staining, flow cytometry, single-cell sequencing, and multiplexed tumor mapping. Future studies will benefit from the consideration of multiple methods and combinations of markers in designing a diagnostic tool for detecting and measuring EMT in patient tumors.
Highlights
During the progression of many solid tumors, cells at the primary tumor site undergo phenotypic changes in response to extracellular stimuli [1,2], one among these being an epithelial-to-mesenchymal transition (EMT)
These works and the application of flow cytometry established a link between the hybrid or intermediate state and increased stemness and decreased patient prognosis using several cell surface markers; this technique is unable to consider the expression of intracellular markers, such as vimentin or ZEB1, which require cell permeabilization
We have employed a multiplexed, multi-round tyramide signal amplification (TSA) staining method using six canonical EMT markers that was used with cell segmentation and morphological features to define an EMT heterogeneity score and overall tumor EMT score in a model system of EMT, and further validated in a cohort of breast cancer patient samples [59]
Summary
During the progression of many solid tumors, cells at the primary tumor site undergo phenotypic changes in response to extracellular stimuli [1,2], one among these being an epithelial-to-mesenchymal transition (EMT). This embryonic developmental program increases invasive and migratory behavior that is advantageous to a metastasizing cancer cell [3], enabling them to disseminate to distant organs. Plasticity within this transition, including its reversal (mesenchymal-to-epithelial transition; MET) to regain epithelial and proliferative characteristics, has been demonstrated in metastatic colonization [4,5]. One or a combination of these methods could be applied to assess patient prognosis by providing rapid and comprehensive analysis of the EMT state and heterogeneity of tumors to inform disease aggression and treatment regimens
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