{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:56:37Z","timestamp":1790657797463,"version":"4.1.0"},"reference-count":26,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"City Of Hope National Medical Center","id":[{"id":"https:\/\/ror.org\/00w6g5w60","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00w6g5w60","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","award":["BCRF-24-089"],"award-info":[{"award-number":["BCRF-24-089"]}],"id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]},{"award":["BCRF-24-089"],"award-info":[{"award-number":["BCRF-24-089"]}],"id":[{"id":"https:\/\/ror.org\/0348ff195","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017192","name":"USC Norris Comprehensive Cancer Center (CORE) Support","doi-asserted-by":"publisher","award":["P30CA014089"],"award-info":[{"award-number":["P30CA014089"]}],"id":[{"id":"10.13039\/100017192","id-type":"DOI","asserted-by":"publisher"}]},{"award":["P30CA014089"],"award-info":[{"award-number":["P30CA014089"]}],"id":[{"id":"https:\/\/ror.org\/01nmyfr60","id-type":"ROR","asserted-by":"publisher"}]},{"name":"USC Michelson Center Convergent Science Institute in Cancer"},{"name":"USC Provost Research Fellowship"},{"name":"Vassiliadis Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Leptomeningeal disease (LMD) is among the most severe complications of metastatic breast cancer, with median survival measured in weeks. Definitive diagnosis relies on neuroimaging and cerebrospinal fluid (CSF) cytology, which carries a false-negative rate of 40\u201350% at a single lumbar puncture. Improved tools for detecting and characterizing tumor cells across systemic and central nervous system (CNS) compartments are urgently needed. Methods: We applied an enrichment-free, fluorescence whole-slide imaging (fWSI)-based liquid biopsy platform to ante-mortem and post-mortem peripheral blood (PB) and CSF from five patients with metastatic breast cancer and confirmed or suspected LMD, collected through the City of Hope LEGACY warm autopsy program. Circulating tumor cells (CTCs) were classified by immunophenotype (cytokeratin [CK], vimentin [VIM], CD45\/CD31) and morphology. Select cells underwent single-cell copy number variation (CNV) profiling by low-pass whole-genome sequencing. Results: Across 23 samples (11 PB, 12 CSF), we identified marked compartmental heterogeneity in CTC burden, phenotype, and genomic architecture. In the one patient (Patient 1) sampled across all four ventricular-to-cisternal CSF sites, CTC frequency declined from proximal to distal compartments (11.4% in the right lateral ventricle to 0.6% at the foramen magnum), a single-patient observation consistent with a proximal-to-distal gradient. Patients with active, untreated LMD showed high CSF CTC incidence with both epithelial and mesenchymal phenotypes, whereas the two patients receiving intrathecal therapy each showed low or absent CSF CTCs; given the small numbers involved and a plausible technical confound in a third patient, we interpret this association cautiously. Single-cell CNV profiling of CSF-derived CTCs across patients with active LMD revealed highly concordant chromosomal aberration profiles, 100% of CK+ CSF CTCs analyzed carried chromosomal aberrations, consistent with, though not formally establishing, expansion of a genomically evolved subclone within the leptomeningeal compartment; PB-derived cells showed substantially greater heterogeneity. In the two patients with paired post-mortem arterial and venous PB, arterial blood showed higher total rare cell counts in both, and higher CK-positive CTC incidence in one (1425.73 vs. undetectable epi.CTC\/mL); the other showed the reverse for this specific metric. Conclusions: Enrichment-free, multi-compartment liquid biopsy reveals a regionally heterogeneous and biologically structured landscape in breast cancer LMD not resolvable by conventional cytology or single-site venous sampling. These findings are consistent with a hypothesis-generating model in which the leptomeningeal space acts as a selective niche for clonally convergent tumor expansion. They also point to the potential of regionally resolved CTC profiling for monitoring LMD treatment response in future, larger cohorts.<\/jats:p>","DOI":"10.3390\/cancers18193124","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:00:34Z","timestamp":1790589634000},"page":"3124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Landscape of Tumor Dissemination in Leptomeningeal Disease: Mapping CTC Plasticity and Regional Heterogeneity Across Blood and CSF Compartments"],"prefix":"10.3390","volume":"18","author":[{"given":"Stephanie N.","family":"Shishido","sequence":"first","affiliation":[{"name":"Michelson Center for Convergent Bioscience, Convergent Science Institute in Cancer (CSI-Cancer), University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baishali","family":"Chaudhuri","sequence":"additional","affiliation":[{"name":"Michelson Center for Convergent Bioscience, Convergent Science Institute in Cancer (CSI-Cancer), University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidur","family":"Mushran","sequence":"additional","affiliation":[{"name":"Michelson Center for Convergent Bioscience, Convergent Science Institute in Cancer (CSI-Cancer), University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5815-7107","authenticated-orcid":false,"given":"Kena","family":"Ihle","sequence":"additional","affiliation":[{"name":"City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujun","family":"Wang","sequence":"additional","affiliation":[{"name":"City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colt A.","family":"Egelston","sequence":"additional","affiliation":[{"name":"City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5353-4338","authenticated-orcid":false,"given":"James","family":"Hicks","sequence":"additional","affiliation":[{"name":"Michelson Center for Convergent Bioscience, Convergent Science Institute in Cancer (CSI-Cancer), University of Southern California, Los Angeles, CA 90089, USA"},{"name":"USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4405-6685","authenticated-orcid":false,"given":"Lisa","family":"Feldman","sequence":"additional","affiliation":[{"name":"City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3435-9110","authenticated-orcid":false,"given":"Eliza","family":"Barragan","sequence":"additional","affiliation":[{"name":"City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2629-4505","authenticated-orcid":false,"given":"Peter","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Michelson Center for Convergent Bioscience, Convergent Science Institute in Cancer (CSI-Cancer), University of Southern California, Los Angeles, CA 90089, USA"},{"name":"USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"},{"name":"Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Catherine and Joseph Aresty Department of Urology, Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1007\/s12032-012-0408-4","article-title":"Breast cancer leptomeningeal metastasis: Propensity of breast cancer subtypes for leptomeninges and the analysis of factors influencing survival","volume":"30","author":"Niwinska","year":"2013","journal-title":"Med. 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