Detection of circulating tumour cell clusters in human glioblastoma

Ilona Krol,Stephanie Anderson,Barbara Maria Szczerba,Niamh Coleman,Heidi Lane,Suzanne Carreira,Juanita Lopez,Martina Maurer,Felix Bachmann,Ramona Scherrer,Francesc Castro-Giner,Rebecca Kristeleit,Nicola Aceto,Thomas Ronald Jeffry Evans,Ruth Plummer,Marc Engelhardt,Sofia Gkountela

doi:10.1038/s41416-018-0186-7

Abstract

Human glioblastoma (GBM) is a highly aggressive, invasive and hypervascularised malignant brain cancer. Individual circulating tumour cells (CTCs) are sporadically found in GBM patients, yet it is unclear whether multicellular CTC clusters are generated in this disease and whether they can bypass the physical hurdle of the blood–brain barrier. Here, we assessed CTC presence and composition at multiple time points in 13 patients with progressing GBM during an open-label phase 1/2a study with the microtubule inhibitor BAL101553. We observe CTC clusters ranging from 2 to 23 cells and present at multiple sampling time points in a GBM patient with pleomorphism and extensive necrosis, throughout disease progression. Exome sequencing of GBM CTC clusters highlights variants in 58 cancer-associated genes including ATM, PMS2, POLE, APC, XPO1, TFRC, JAK2, ERBB4 and ALK. Together, our findings represent the first evidence of the presence of CTC clusters in GBM.

Highlights

Human glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults.[1]
Circulating tumour cells (CTCs) detection strategy in GBM patients Patients selected for CTCs investigation were part of an ongoing open-label Phase 1/2a study arm of oral BAL101553, a watersoluble microtubule inhibitor, in adult individuals with recurrent or progressive GBM or high-grade glioma
Radiological imaging determined that none of the 13 patients enroled in the study developed extracranial metastasis, and no association was observed between functional magnetic resonance imaging (MRI) volume and the presence of CTCs, most likely due to the small patient cohort (n = 13) (Supplementary Fig. 3)

Summary

Introduction

Human glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults.[1] Yet, despite its characteristic invasive features and hypervascularity determined by angiogenic recruitment, only 0.4–2% of GBM patients develop metastasis outside of the central nervous system.[2] The rarity of these metastatic events has been attributed to the short-term survival of patients after initial GBM diagnosis, leaving insufficient time for establishment of extracranial lesions, as well as to the presence of the blood–brain barrier, which physically separates the brain from the rest of the body.[3] Circulating tumour cells (CTCs) are cancer cells that detach from a primary tumour lesion or a metastatic deposit and enter the bloodstream.[4] individual CTCs have been sporadically observed in GBM,[5,6,7,8] it is unclear whether multicellular CTC clusters[9] are generated and are able to pass through the blood-brain barrier in patients with GBM

Methods

Results

Conclusion