Abstract

Most cancer metastases exhibit mutational profiles similar to those of the primary tumor. However, the nongenetic mechanisms driving metastasis remain poorly understood. Here, we show that lineage trans-differentiation is a hallmark of cancer metastasis. Bioinformatic tools capable of reconstructing cancer phenotypic evolutionary trajectories at single-cell resolution were developed, revealing a progressive loss of transcriptional and epigenomic lineage fidelity in cancer cells as they evolve toward metastasis. During premetastatic evolution, cells undergo de-differentiation into a fetal-like state. The mis-expression of alternative-lineage gene programs during re-differentiation from this fetal-like state leads to the formation of trans-differentiated metastatic cells. This trans-differentiation, rather than fetal-like transcription, constitutes a key feature of metastasis in both humans and mice. In clinical samples, trans-differentiation correlates with histopathological grade, metastatic potential, and patient survival. Additionally, trans-differentiation is associated with gain of oncogenic mitogen-activated protein kinase (MAPK) signaling and can be reversed through MAPK inhibition. These findings offer a detailed account of metastatic cancer evolution driven by epigenetic reprogramming while also uncovering the molecular mechanisms underlying this process.