Do cancer cells undergo phenotypic switching? The case for imperfect cancer stem cell markers

TL;DR

This paper challenges the idea that cancer cells switch phenotypes by proposing that imperfect markers and sorting errors explain observed marker reversibility, supported by a mathematical model.

Contribution

It introduces a mathematical model accounting for marker imperfection and sorting errors, offering an alternative explanation to phenotypic switching in cancer cells.

Findings

Reversible marker expression does not necessarily indicate phenotypic switching.

Imperfect markers can lead to misclassification of cancer stem cells.

Sorting errors contribute to the observed phenotypic variability.

Abstract

The identification of cancer stem cells in vivo and in vitro relies on specific surface markers that should allow to sort cancer cells in phenotypically distinct subpopulations. Experiments report that sorted cancer cell populations after some time tend to express again all the original markers, leading to the hypothesis of phenotypic switching, according to which cancer cells can transform stochastically into cancer stem cells. Here we explore an alternative explanation based on the hypothesis that markers are not perfect and are thus unable to identify all cancer stem cells. Our analysis is based on a mathematical model for cancer cell proliferation that takes into account phenotypic switching, imperfect markers and error in the sorting process. Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching.