A liquid biopsy for detecting circulating mesothelial precursor cells: A new biomarker for diagnosis and prognosis in mesothelioma

Bill T V Duong; Licun Wu; Brenda J Green; Fatemeh Bavaghar-Zaeimi; Zongjie Wang; Mahmoud Labib; Yuxiao Zhou; Fernando J P Cantu; Thurgaa Jeganathan; Sandra Popescu; Jennifer Pantea; Marc de Perrot; Shana O Kelley

doi:10.1016/j.ebiom.2020.103031

A liquid biopsy for detecting circulating mesothelial precursor cells: A new biomarker for diagnosis and prognosis in mesothelioma

EBioMedicine. 2020 Nov:61:103031. doi: 10.1016/j.ebiom.2020.103031. Epub 2020 Oct 9.

Authors

Affiliations

¹ Department of Chemistry, University of Toronto, 80 St George St., Toronto, Ontario M5S 3H6, Canada.
² Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, 101 College St., Toronto, Ontario M5G 1L7, Canada.
³ Institute for Biomaterials and Biomedical Engineering, University of Toronto, 164 College St., Toronto, Ontario M5S 3G9, Canada.
⁴ Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, 101 College St., Toronto, Ontario M5G 1L7, Canada; Division of Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Centre, University Health Network, 200 Elizabeth St., Toronto, Ontario M5G 2C4, Canada.
⁵ Institute for Biomaterials and Biomedical Engineering, University of Toronto, 164 College St., Toronto, Ontario M5S 3G9, Canada; The Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, 10 King's College Rd., Toronto, Ontario M5S 3G4, Canada.
⁶ Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada.
⁷ Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, 101 College St., Toronto, Ontario M5G 1L7, Canada; Division of Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Centre, University Health Network, 200 Elizabeth St., Toronto, Ontario M5G 2C4, Canada; Department of Immunology, University of Toronto, 27 King's College Circle, Toronto, Ontario M5S 1A1, Canada. Electronic address: marc.deperrot@uhn.ca.
⁸ Department of Chemistry, University of Toronto, 80 St George St., Toronto, Ontario M5S 3H6, Canada; Institute for Biomaterials and Biomedical Engineering, University of Toronto, 164 College St., Toronto, Ontario M5S 3G9, Canada; Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada; Department of Biochemistry, University of Toronto, 27 King's College Circle, Toronto, Ontario M5S 1A1, Canada. Electronic address: shana.kelley@utoronto.ca.

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer related to asbestos exposure. Early diagnosis is challenging due to generic symptoms and a lack of biomarkers. We previously demonstrated that mesothelial precursor cells (MPC) characterized by mesothelin (MSLN)+CD90+CD34+ could be implicated in the development of mesothelioma after asbestos exposure. Here, we aimed to determine the clinical significance of detecting MPC in blood for early-stage diagnosis and prognosis of mesothelioma.

Methods: Due to the rarity of MPC in blood, it is challenging to identify this cell population using conventional techniques. Hence, we have developed a microfluidic liquid biopsy platform called MesoFind that utilizes an immunomagnetic, mesothelin capture strategy coupled with immunofluorescence to identify rare populations of cells at high sensitivity and precision. To validate our technique, we compared this approach to flow cytometry for the detection of MPC in murine blood and lavage samples. Upon successful validation of the murine samples, we then proceeded to examine circulating MPC in 23 patients with MPM, 23 asbestos-exposed individuals (ASB), and 10 healthy donors (HD) to evaluate their prognostic and diagnostic value.

Finding: MPC were successfully detected in the blood of murine samples using MesoFind but were undetectable with flow cytometry. Circulating MPC were significantly higher in patients with epithelioid MPM compared to HD and ASB. The MPC subpopulation, MSLN+ and CD90+, were upregulated in ASB compared to HD suggesting an early role in pleural damage from asbestos. The MPC subpopulation, MSLN+ and CD34+, in contrast, were detected in advanced MPM and associated with markers of poor prognosis, suggesting a predominant role during cancer progression.

Interpretation: The identification of circulating MPC presents an attractive solution for screening and early diagnosis of epithelioid mesothelioma. The presence of different subtypes of MPC have a prognostic value that could be of assistance with clinical decisions in patients with MPM.

Funding: Princess Margaret Hospital Foundation Mesothelioma Research Fund, Toronto General & Western Hospital Foundation.

Keywords: Clinical prognosis; Diagnostic biomarker; Liquid biopsy; Mesothelial precursor cells; Mesothelioma; Molecular profiling.

MeSH terms

Aged
Aged, 80 and over
Animals
Asbestos / adverse effects
Biomarkers, Tumor*
Cell Line
Disease Models, Animal
Female
Gene Expression Profiling / methods
Humans
Liquid Biopsy* / methods
Liquid Biopsy* / standards
Male
Mesothelin
Mesothelioma / diagnosis*
Mesothelioma / etiology
Mice
Middle Aged
Neoplasm Grading
Neoplasm Metastasis
Neoplasm Staging
Neoplastic Cells, Circulating / pathology*
Occupational Exposure / adverse effects
Prognosis
Reproducibility of Results
Transcriptome

Substances

Biomarkers, Tumor
MSLN protein, human
Msln protein, mouse
Asbestos
Mesothelin

Grants and funding

R33 CA204574/CA/NCI NIH HHS/United States