LGR5− cells seed colorectal cancer metastases and produce stemlike LGR5+ outgrowth-promoting cells.
Major Finding: LGR5− cells seed colorectal cancer metastases and produce stemlike LGR5+ outgrowth-promoting cells.
Concept: The plasticity of LGR5− cells was independent of factors associated with a stemness-promoting niche.
Impact: This work suggests that cancer stem cells, while required for outgrowth, do not initiate metastasis.
In the predominant model of metastatic colorectal cancer, metastases are thought to be seeded by cancer stem cells (CSC) characterized by expression of the marker LGR5. However, via experiments using a mouse model of colorectal cancer and human tumor xenografts, Fumagalli, Oost, and colleagues discovered that this may not be the case. In fact, multiphoton microscopy showed that the majority of migratory cells in the mouse model were LGR5−, implying that most migratory cells were in a state more differentiated than prior models would have predicted. Blood analysis revealed that these LGR5− cells, which also did not express other markers of stemness, were able to escape into the bloodstream, a precursor to metastasis; indeed, the vast majority of circulating cancer cells and all single-cell liver metastases were LGR5−. Although these LGR5− cells were capable of seeding metastases, further investigation revealed that the appearance of LGR5+ cells was required for metastatic outgrowth: Metastases founded by LGR5− cells regressed in the absence of LGR5+ cells. Interestingly, LGR5− cells appeared to have an intrinsic plasticity, enabling them to become LGR5+ cells even in the absence of molecular signals (for example, HGF and FGF) typically thought necessary for the reestablishment of stem cell–like states, although the presence of such factors did enhance plasticity. Thus, unexpectedly, the cellular plasticity of metastasis-seeding LGR5− cells is niche independent and does not require a stemness-promoting microenvironment. In summary, contrary to what has previously been suggested, CSCs may not directly seed colorectal cancer metastases; instead, LGR5− cells initiate metastases, then undergo a transition to a more stemlike LGR5+ state that supports metastatic outgrowth.
Fumagalli A, Oost KC, Kester L, Morgner J, Bornes L, Bruens L, et al. Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell Stem Cell 2020 Mar 12 [Epub ahead of print].
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