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The lack of reproducible in vitro and in vivo models has prevented the development of novel, LM\u2010specific therapies. Although LM allows for longitudinal sampling of floating cancer cells with a spinal tap, attempts to culture patient\u2010derived leptomeningeal cancer cells have not been successful.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>We, therefore, employ leptomeningeal derivatives of human breast and lung cancer cell lines that reproduce both floating and adherent phenotypes of human LM in vivo and in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>We introduce a trypsin\/EDTA\u2010based fractionation method to reliably separate the two cell subsets and demonstrate that in vitro cultured floating cells have decreased proliferation rate, lower ATP content, and are enriched in distinct metabolic signatures. Long\u2010term fractionation and transcriptomic analysis suggest high degree plasticity between the two phenotypes in vitro. Floating cells colonize mouse leptomeninges more rapidly and associate with shortened survival. In addition, patients harboring LM diagnosed with CSF disease alone succumbed to the disease earlier than patients with adherent (MRI positive) disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Together, these data support mechanistic evidence of a metabolic adaptation that allows cancer cells to thrive in their natural environment but leads to death in vitro.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cnr2.1236","type":"journal-article","created":{"date-parts":[[2020,1,30]],"date-time":"2020-01-30T04:31:22Z","timestamp":1580358682000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Leptomeningeal metastatic cells adopt two phenotypic states"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3228-2896","authenticated-orcid":false,"given":"Jan","family":"Remsik","sequence":"first","affiliation":[{"name":"Human Oncology and Pathogenesis Program Memorial 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