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Summary Epithelial-to-mesenchymal transition (EMT) has long been thought to be crucial for metastasis. Recently a study challenged this idea by demonstrating that metastases were seeded by tumor cells that were not marked by an EMT lineage-tracing reporter on the basis of the expression of the mesenchymal marker fsp1. However, the results of this study and their interpretation are under debate. Here, we combine the lineage-tracing reporter with our real-time EMT-state reporter and show that the fsp1-based EMT lineage-tracing reporter does not mark all disseminating mesenchymal cells with metastatic potential. Our findings demonstrate that fsp1-mediated lineage tracing does not allow any conclusions about the requirement of EMT for metastasis. Instead our data are fully consistent with previous reports that EMT is not a binary phenomenon but rather a spectrum of cellular states., Graphical Abstract, Highlights • Combination of historical and dynamic EMT reporter • Not all cells undergoing EMT are labeled by the fsp1-mediated lineage-tracing mark • The pool of mesenchymal cells that are not traced by fsp1 have metastatic potential • EMT is a spectrum of cell states and gene expressions rather than a binary process, Bornes et al. use a combination of fsp1-based lineage-tracing and E-cadherin-based real-time EMT-state reporter. They demonstrate that the majority of disseminating mesenchymal cells in breast tumors are not labeled by the fsp1-mediated lineage-tracing mark but do have metastatic potential. These findings uphold the role of EMT in metastasis.

Summary Calorie restriction (CR) extends lifespan through several intracellular mechanisms, including increased DNA repair, leading to fewer DNA mutations that cause age-related pathologies. However, it remains unknown how CR acts on mutation retention at the tissue level. Here, we use Cre-mediated DNA recombination of the confetti reporter as proxy for neutral mutations and follow these mutations by intravital microscopy to identify how CR affects retention of mutations in the intestine. We find that CR leads to increased numbers of functional Lgr5+ stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying neutral or Apc mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine., Graphical Abstract, Highlights • Calorie restriction increases stem cell numbers in intestinal crypts • Increased stem cell numbers per crypt strengthen stem cell competition • Mutant stem cells encounter more wild-type competitors upon calorie restriction • More wild-type competitors reduce retention of mutant stem cells in the intestine, Calorie restriction increases the number of stem cells in intestinal crypts. Bruens et al. show that this increase results in stronger stem cell competition. Consequently, mutated stem cells encounter more wild-type competitors, which decreases the chance that these mutated stem cells are retained in the intestinal epithelium.