The circulating tumor microenvironment in small-cell lung cancer: Vimentin-positive circulating tumor endothelial cells as drivers of metastasis and poor prognosis in a large cohort study.

Aggressive progression of small-cell lung cancer (SCLC) is orchestrated by a dynamic tumor microenvironment (TME). However, profiling this ecosystem remains a major constraint. The critical role of CD31+ aneuploid circulating tumor endothelial cells expressing vimentin (i.e. Vim+ CTECs amid Endo-MT process) in promoting SCLC metastasis was systematically investigated in this study. Large cohorts of 142 treatment-naïve SCLC patients were prospectively enrolled in the current multicenter study. Patients were subjected to the first-line platinum-based chemotherapy alone or combined with immunotherapy or radiotherapy as indicated. Both Vim- and Vim+ CTECs were longitudinally co-detected at baseline (t0), after two cycles (t1), and post-complete treatment (t2). A high baseline CTEC count (≥ 15/6 mL) correlated with a higher incidence of liver metastasis and a lower initial disease control rate. Positive detection of Vim+ CTECs (t0) was also significantly associated with liver metastasis. Multivariate analysis identified post-treatment Vim+ CTECs (t1-2) as an independent prognostic factor for both inferior progression-free survival (PFS) and overall survival (OS). The metastasis-promoting function of endothelial vimentin was further validated using in vivo liver metastasis mouse models and in vitro vimentin-knockdown endothelial cell lines. Mechanistically, endothelial vimentin was essential for promoting SCLC cell proliferation, migration, liver metastasis in vivo, and invasion in vitro, which were abrogated by vimentin knockdown. Vim+ CTECs serve as a key driver of tumor metastasis in SCLC. Detection of Vim+ CTECs constitutes a novel paradigm for real-time risk stratification and outcome prediction.