Functional drug susceptibility testing using single-cell mass predicts treatment outcome in patient-derived cancer neurosphere models

Max A Stockslager; Seth Malinowski; Mehdi Touat; Jennifer C Yoon; Jack Geduldig; Mahnoor Mirza; Annette S Kim; Patrick Y Wen; Kin-Hoe Chow; Keith L Ligon; Scott R Manalis

doi:10.1016/j.celrep.2021.109788

Functional drug susceptibility testing using single-cell mass predicts treatment outcome in patient-derived cancer neurosphere models

Cell Rep. 2021 Oct 5;37(1):109788. doi: 10.1016/j.celrep.2021.109788.

Authors

Affiliations

¹ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA, USA.
² Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
³ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
⁴ Koch Institute for Integrative Cancer Research, Cambridge, MA, USA.
⁵ Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA USA.
⁷ Center for Patient-Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA; Center for Patient-Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: keith_ligon@dfci.harvard.edu.
⁹ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: srm@mit.edu.

PMID: 34610309
DOI: 10.1016/j.celrep.2021.109788

Abstract

Functional precision medicine aims to match individual cancer patients to optimal treatment through ex vivo drug susceptibility testing on patient-derived cells. However, few functional diagnostic assays have been validated against patient outcomes at scale because of limitations of such assays. Here, we describe a high-throughput assay that detects subtle changes in the mass of individual drug-treated cancer cells as a surrogate biomarker for patient treatment response. To validate this approach, we determined ex vivo response to temozolomide in a retrospective cohort of 69 glioblastoma patient-derived neurosphere models with matched patient survival and genomics. Temozolomide-induced changes in cell mass distributions predict patient overall survival similarly to O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation and may aid in predictions in gliomas with mismatch-repair variants of unknown significance, where MGMT is not predictive. Our findings suggest cell mass is a promising functional biomarker for cancers and drugs that lack genomic biomarkers.

Keywords: cancer; cell mass; cell size; functional drug susceptibility testing; glioblastoma.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents, Alkylating / pharmacology*
Antineoplastic Agents, Alkylating / therapeutic use
Biomarkers, Tumor / genetics
Brain Neoplasms / drug therapy
Brain Neoplasms / mortality
Brain Neoplasms / pathology*
Cell Size / drug effects*
DNA Methylation
DNA Modification Methylases / genetics
DNA Modification Methylases / metabolism
DNA Repair Enzymes / genetics
DNA Repair Enzymes / metabolism
Drug Screening Assays, Antitumor / methods
Glioblastoma / drug therapy
Glioblastoma / mortality
Glioblastoma / pathology*
Humans
Models, Biological
Neoplasm Grading
Promoter Regions, Genetic
Retrospective Studies
Single-Cell Analysis / methods*
Survival Rate
Temozolomide / pharmacology
Temozolomide / therapeutic use
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

Antineoplastic Agents, Alkylating
Biomarkers, Tumor
Tumor Suppressor Proteins
DNA Modification Methylases
MGMT protein, human
DNA Repair Enzymes
Temozolomide

Abstract

Publication types

MeSH terms

Substances

Grants and funding