Diagnostic leukapheresis reveals distinct phenotypes of NSCLC circulating tumor cells

TY - JOUR

T1 - Diagnostic leukapheresis reveals distinct phenotypes of NSCLC circulating tumor cells

AU - Rieckmann, Lisa-Marie

AU - Spohn, Michael

AU - Ruff, Lisa

AU - Agorku, David

AU - Becker, Lisa

AU - Borchers, Alina

AU - Krause, Jenny

AU - O'Reilly, Roisin

AU - Hille, Jurek

AU - Velthaus-Rusik, Janna-Lisa

AU - Beumer, Niklas

AU - Günther, Armin

AU - Willnow, Lena

AU - Imbusch, Charles D

AU - Iglauer, Peter

AU - Simon, Ronald

AU - Franzenburg, Sören

AU - Winter, Hauke

AU - Thomas, Michael

AU - Bokemeyer, Carsten

AU - Gagliani, Nicola

AU - Krebs, Christian F

AU - Sprick, Martin

AU - Hardt, Olaf

AU - Riethdorf, Sabine

AU - Trumpp, Andreas

AU - Stoecklein, Nikolas H

AU - Peine, Sven

AU - Rosenstiel, Philipp

AU - Pantel, Klaus

AU - Loges, Sonja

AU - Janning, Melanie

N1 - © 2024. The Author(s).

PY - 2024/5/8

Y1 - 2024/5/8

N2 - BACKGROUND: Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA's full potential, this study introduces a novel approach for CTC enrichment from DLAs.METHODS: DLA was applied to six advanced stage NSCLC patients. For an unbiased CTC enrichment, a two-step approach based on negative depletion of hematopoietic cells was used. Single-cell (sc) whole-transcriptome sequencing was performed, and CTCs were identified based on gene signatures and inferred copy number variations.RESULTS: Remarkably, this innovative approach led to the identification of unprecedented 3,363 CTC transcriptomes. The extensive heterogeneity among CTCs was unveiled, highlighting distinct phenotypes related to the epithelial-mesenchymal transition (EMT) axis, stemness, immune responsiveness, and metabolism. Comparison with sc transcriptomes from primary NSCLC cells revealed that CTCs encapsulate the heterogeneity of their primary counterparts while maintaining unique CTC-specific phenotypes.CONCLUSIONS: In conclusion, this study pioneers a transformative method for enriching CTCs from DLA, resulting in a substantial increase in CTC numbers. This allowed the creation of the first-ever single-cell whole transcriptome in-depth characterization of the heterogeneity of over 3,300 NSCLC-CTCs. The findings not only confirm the diagnostic value of CTCs in monitoring tumor heterogeneity but also propose a CTC-specific signature that can be exploited for targeted CTC-directed therapies in the future. This comprehensive approach signifies a major leap forward, positioning CTCs as a key player in advancing our understanding of cancer dynamics and paving the way for tailored therapeutic interventions.

AB - BACKGROUND: Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA's full potential, this study introduces a novel approach for CTC enrichment from DLAs.METHODS: DLA was applied to six advanced stage NSCLC patients. For an unbiased CTC enrichment, a two-step approach based on negative depletion of hematopoietic cells was used. Single-cell (sc) whole-transcriptome sequencing was performed, and CTCs were identified based on gene signatures and inferred copy number variations.RESULTS: Remarkably, this innovative approach led to the identification of unprecedented 3,363 CTC transcriptomes. The extensive heterogeneity among CTCs was unveiled, highlighting distinct phenotypes related to the epithelial-mesenchymal transition (EMT) axis, stemness, immune responsiveness, and metabolism. Comparison with sc transcriptomes from primary NSCLC cells revealed that CTCs encapsulate the heterogeneity of their primary counterparts while maintaining unique CTC-specific phenotypes.CONCLUSIONS: In conclusion, this study pioneers a transformative method for enriching CTCs from DLA, resulting in a substantial increase in CTC numbers. This allowed the creation of the first-ever single-cell whole transcriptome in-depth characterization of the heterogeneity of over 3,300 NSCLC-CTCs. The findings not only confirm the diagnostic value of CTCs in monitoring tumor heterogeneity but also propose a CTC-specific signature that can be exploited for targeted CTC-directed therapies in the future. This comprehensive approach signifies a major leap forward, positioning CTCs as a key player in advancing our understanding of cancer dynamics and paving the way for tailored therapeutic interventions.

KW - Neoplastic Cells, Circulating/pathology

KW - Humans

KW - Carcinoma, Non-Small-Cell Lung/genetics

KW - Leukapheresis

KW - Lung Neoplasms/genetics

KW - Biomarkers, Tumor

KW - Phenotype

KW - Single-Cell Analysis/methods

KW - Transcriptome

KW - Epithelial-Mesenchymal Transition/genetics

KW - Gene Expression Profiling

KW - Cell Line, Tumor

U2 - 10.1186/s12943-024-01984-2

DO - 10.1186/s12943-024-01984-2

M3 - Letter

C2 - 38720314

VL - 23

SP - 93

JO - MOL CANCER

JF - MOL CANCER

SN - 1476-4598

IS - 1

ER -