Opportunities and Challenges in Implementation of Multiparameter Single Cell Analysis Platforms for Clinical Translation

Abstract

The high‐content interrogation of single cells with platforms optimized for the multiparameter characterization of cells in liquid and solid biopsy samples can enable characterization of heterogeneous populations of cells ex vivo. Doing so will advance the diagnosis, prognosis, and treatment of cancer and other diseases. However, it is important to understand the unique issues in resolving heterogeneity and variability at the single cell level before navigating the validation and regulatory requirements in order for these technologies to impact patient care. Since 2013, leading experts representing industry, academia, and government have been brought together as part of the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium to foster the potential of high‐content data integration for clinical translation.

Modeling the Effect of the Metastatic Microenvironment on Phenotypes Conferred by Estrogen Receptor Mutations Using a Human Liver Microphysiological System

“…The use of hyperplexed (use of >7) fluorescence-based biomarkers in the same tissue 63 has accelerated the development of computational pathology tools to understand the heterogeneity within TMEs. This information is used as a guide to optimize the physiological relevance of TME’s engineered into MPS models and to develop systems biology models of tumor progression and predictive models of cancer recurrence 63–65 .…”

National Cancer Institute Alliance for nanotechnology in cancer—Catalyzing research and translation toward novel cancer diagnostics and therapeutics

“…This could be achieved through identifying "niche" applications which are uniquely positioned to benefit from nanotechnology and do not have viable contemporary solutions, expanding the scope of monotherapies to combination therapies delivering two or more synergistic drugs and/or engaging more than one treatment modalities. These strategies can be further facilitated by the implementation of companion diagnostics relying on testing the strength of the Enhanced Permeability and Retention (EPR) effect responsible for nanoparticle accumulation in solid tumors, and resulting in identification of patients for whom nanomedicines may be most effective (Ehlerding, Grodzinski, Cai, & Liu, 2018;Keating et al, 2018;Lee et al, 2017;Miller et al, 2015;Wong, Siah, & Lo, 2018). F I G U R E 1 1 The initial NCI funding and additional funding leveraged by funding to four Alliance CCNEs, which have been funded for all Phases of the program (California Institute of Technology, Northwestern University, Stanford University, and University of North Carolina at Chapel Hill).…”

Selection and optimization of enzyme reporters for chemical cytometry

“…Analysis of this heterogeneity amongst cells within a population is critical to provide deeper understanding of cell behavior in response to intrinsic differences and extrinsic inputs in both normal and diseased states. (Keating et al, 2018;Mincarelli et al, 2018; Wang and yet face the challenge of loading probes into viable cells. (Goryashchenko et al, 2018;Kovarik and Allbritton, 2011;Rowland et al, 2015) Proximity ligation assays have also been used to assess enzyme activity, but this method relies on genetic transformation of cells, a difficulty when utilizing primary samples obtained directly from a patient.…”

“…in addition to the diseased cells of interest), compounding existing challenges with low sample sizes. (Keating et al, 2018) Methods to overcome these difficulties would be of high utility for single-cell analysis.…”