How important is EMT for cancer metastasis?

Abstract

Epithelial-to-mesenchymal transition (EMT), a biological phenomenon of cellular plasticity initially reported in embryonic development, has been increasingly recognized for its importance in cancer progression and metastasis. Despite tremendous progress being made in the past 2 decades in our understanding of the molecular mechanism and functional importance of EMT in cancer, there are several mysteries around EMT that remain unresolved. In this Unsolved Mystery, we focus on the variety of EMT types in metastasis, cooperative and collective EMT behaviors, spatiotemporal characterization of EMT, and strategies of therapeutically targeting EMT. We also highlight new technical advances that will facilitate the efforts to elucidate the unsolved mysteries of EMT in metastasis.

Fig 1. Diverse EMT types are linked to different degrees of plasticity and metastatic potential.

(A) The spectrum of EMT subtypes with different functional qualities that fall between the classical epithelial (E) and mesenchymal (M) phenotypes, each of these subtypes are defined by the degree of different EMT states through the EMT process. Most of them are easily reversable through MET, except the extreme EMT. (B) Classification of EMT into 4 major types with different qualities determining their metastatic potential. (1) Partial EMT involves a hybrid mixture of E and M markers. These are cells in transition between E and M states and have cellular plasticity. This type of EMT is found in collective invasion regions and has metastatic colonization ability. (2) Intermediate EMT refers to a hybrid state that reduces most prominent E markers, gains M markers, but does not reach an extreme M state. It preserves high cellular plasticity, allowing it to revert to MET, and it is endowed with stem cell programs, invasion, and aggressive metastatic ability. (3) Extreme EMT exhibits high expression of classic M markers. This type is highly invasive and chemoresistant but has reduced metastatic abilities due to restricted plasticity in reactivating proliferative states. (4) Ameboid EMT represents a state beyond the M state. These cells exit the EMT transdifferentiation and detour into undifferentiated ameboid-like cells. This state is characterized by high mechanoplasticity, migration, and metastasis ability. Illustration was created in part with Biorender.com.

Fig 2. Main implications of the different EMT types in metastasis.

(1) Partial EMT is implicated in primary tumor cell dissemination, collective migration, cluster survival in circulation, extravasation, and metastasis colonization. (2) Intermediate EMT has higher plasticity and stemness with higher capacity of tumor initiation in distant metastatic sites. (3) Extreme EMT facilitates tumor cell dissemination in primary tumors, as they are highly invasive. This type of EMT also has high chemoresistance during tumor progression. Its role is less relevant at distant organ sites. (4) Ameboid EMT has particular relevance in primary tumor escape and secondary organ extravasation due to squeezing mobility through reduced tissues spaces.

Fig 3. Strategies to target EMT and cellular plasticity in metastasis.

Many oncogenic drugs are currently under development that target EMT upstream pathways, such as TGF-β, Wnt, FGF, or NFκB, although it will be challenging to discern how much of the therapeutic benefit is due to inhibition of EMT. An alternative strategy is to drive cells in highly metastatic hybrid or intermediate EMT states into differentiating into an epithelial state or into a terminally mesenchymal or post-mesenchymal state, such as adipocytes. The third approach identifies vulnerabilities of cells at the intermediate or hybrid EMT states as potential therapeutic opportunities, either as single targets or in combination with other standard therapies. The fourth strategy is to limit cellular plasticity and inter-conversion between intermediate EMT states by targeting epigenetic regulators or molecular memory circuits that confer such plasticity to tumor cells.