Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression

TLDR

Metastatic disease is a leading cause of cancer death, yet the factors controlling tumor cell metastasis remain incompletely understood. The study investigates this by employing tumor cell lines from mice that develop metastatic lung adenocarcinoma driven by mutant K‑ras and p53. Using these lines, the authors examined how extracellular signals influence metastasis regulation. They found that metastasis‑prone cells undergo reversible EMT driven by loss of the miR‑200 family, and that forced miR‑200 expression blocks EMT, invasion, and metastasis, showing that miR‑200 levels modulated by contextual cues govern tumor metastasis.

Abstract

Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53 . Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in three-dimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-β or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize, and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that tumor cell metastasis is regulated by miR-200 expression, which changes in response to contextual extracellular cues.