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.</p

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.</p

Related Article from Acute Infection Induces a Metastatic Niche: A Double Menace for Cancer Patients

Related Article from Acute Infection Induces a Metastatic Niche: A Double Menace for Cancer Patient

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.</p

(color online) Densities of five species in Monte Carlo simulation. <i>L</i> = 200,<i>k</i>_{<i>i</i>, <i>j</i>} = 1.

<p>After about 500 time steps, the species <i>S</i>₄ and <i>S</i>₃ extinct and species <i>S</i>₁, <i>S</i>₂ and <i>S</i>₅ coexist.</p

(color online). The relationships of five species in the Jungle game.

<p>Arrows point from predator to prey. <i>S</i>₁ and <i>S</i>₂ can prey three species and be hunt by one species; <i>S</i>₃ can prey two species and be hunt by two species; <i>S</i>₄ and <i>S</i>₅ can prey one species and be hunt by three species.</p

The area of region II in Fig 3 with different <i>p</i>₁.

<p>There exists <i>P</i> ≈ 1.149 making the smallest area at <i>p</i>₁ = <i>P</i>. When <i>p</i>₁ < <i>P</i>, the area decreases with the increasing <i>p</i>₁; when <i>p</i>₁ > <i>P</i>, the area increases with the increasing <i>p</i>₁.</p

(color online) Coexistence of species in example 1 using Monte Carlo simulation. <i>L</i> = 400.

<p>All five species coexist in the red region. Species <i>S</i>₁<i>S</i>₄<i>S</i>₅ coexist in the orange region. Species <i>S</i>₁<i>S</i>₂<i>S</i>₅ coexist in the light yellow region. Species <i>S</i>₁<i>S</i>₃<i>S</i>₅ coexist in the deep yellow region. Only <i>S</i>₅ remains in the green region. Only <i>S</i>₁ or <i>S</i>₂ remains in the blue region.</p

(color online) Densities of five species in Monte Carlo simulation. <i>L</i> = 200,<i>k</i>_{<i>i</i>, <i>j</i>} = 1.

<p>After about 500 time steps, the species <i>S</i>₄ and <i>S</i>₃ extinct and species <i>S</i>₁, <i>S</i>₂ and <i>S</i>₅ coexist.</p

The biodiversity of the Jungle game in the first example.

<p>Species <i>S</i>₁, <i>S</i>₂ and <i>S</i>₅ coexist in region I; all five species coexist in region II; and species <i>S</i>₁, <i>S</i>₄ and <i>S</i>₅ coexist in region III.</p