Cellular plasticity – the ability to dynamically adapt to various changing biochemical
and biomechanical, intracellular and extracellular conditions – is a hallmark of cancer
aggressiveness. Metastasis, tumor relapse, and resistance against various therapies
are manifestations of this multi-faceted phenomenon. Modes of tumor cell plasticity
include transitions among phenotypes on the epithelial-mesenchymal spectrum, different
subsets of cancer stem cells (CSCs) and non-CSCs, and various metabolic states. These
modes depend on a complex interplay between multistable genetic networks, epigenetic
regulation and cellular physiology. Furthermore, there is a reciprocal interaction
between tumor cell plasticity and plasticity of the microenvironment, as illustrated
for example in the alternative polarization states available for macrophages and CD4+
T-helper cells.
Recent in silico, in vitro, and in vivo studies have highlighted that all the processes
mentioned above - Epithelial-to-Mesenchymal Transition (EMT), macrophage polarization,
and metabolic flexibility related to the Warburg effect - are not binary as originally
hypothesized. Instead, cells can acquire a variety of hybrid phenotype(s) with mixed
molecular and cellular properties. The hybrid epithelial/mesenchymal (E/M) phenotypes
may underpin collective cell migration during metastasis, leading to clusters of circulating
tumor cells or emboli, and are typically more ‘stem-like’ and aggressive than cells
on either end of the spectrum of this Epithelial-Mesenchymal Plasticity (EMP). Similarly,
metabolic phenotypes exhibiting hybrid glycolytic/oxidative phosphorylation processes
can drive aggressiveness and therapy resistance. Finally, reversible transitions among
non-CSCs and different subsets of CSCs represent a population-level equilibrium maintained
among various tumor cell populations.
Progress in charting the underlying regulatory networks mediating these interconnected
manifestations of plasticity has facilitated detailed computational studies to identify
various nodes in these networks that can potentially serve as biomarkers or therapeutic
targets. However, a comprehensive characterization of the dynamics of these transitions
and other associated traits such as drug resistance, immune evasion, epigenetic modifications,
genetic instability, and cell migration and invasion, and identification of the molecular
factors that coordinate these associations, remains incomplete. In this Research Topic,
we focus on the molecular and cellular aspects of the multi-dimensional nature of
tumor cell plasticity and its implications for cancer progression, metastasis, and
tumor relapse. The crucial contributions contained herein cover a broad range of topics
related to characterizing the multifaceted dynamics of cellular plasticity.
Sadeghi et al. (2020) performed an integrative analysis to establish the role of EMT
within the breast cancer acidic microenvironment. A partial EMT phenotype was observed
in the acid-adapted cellular populations, indicating cellular plasticity leading to
metastatic competence. The authors also proposed the S100A6 and S100B proteins as
key players during the acid-induced EMT phenotypic alteration. Tashireva et al. (2020)
categorized molecular subtypes of breast cancer to evaluate stemness and epithelial-mesenchymal
transition (EMT) in single tumor cells (STCs). They found that in comparison to mesenchymal-like
STCs, cells with epithelial-like morphology more effectively contribute towards breast
cancer metastasis. Hellinger et al. (2019) identified an interaction of CYR61 with
metastasis-associated protein S100A4 in invasive breast cancer cells. Their findings
suggest that inhibiting EMT induced CYR61 reduces ERK1/2 phosphorylation, thereby
suppressing S100A4 and hence invasiveness in mesenchymal-ransformed breast cancer
cells. In a breast cancer case report, Ruan et al. (2019) focused on a rare pathological
phenomenon called cell cannibalism. The authors reported a high frequency of cell-in-cell
(CIC) structures with considerable heterogeneity associated with active cell proliferation
and poor prognosis. Teo et al. (2020) utilized the 4T1 murine model of TNBC to reveal
that Inhibitor of Differentiation Protein (ID1) is expressed in rare neoplastic cells
within ER-negative breast cancers. They unveiled a novel mechanism where ID proteins
negatively regulate Robo1, activating a Myc transcriptional program. Thong et al.
(2020) used single-cell RNA-sequencing to quantify cell state distributions and hybrid
stem cell states of the normal mammary (NM) gland throughout the developmental stages
of breast and cancer. Their analysis highlighted the phenotypic plasticity of normal
mammary stem cells, where E/M hybrids are the most developmentally immature type and
play an important role in mammary morphogenesis. Among the breast cancer subtypes,
basal tumors expressed a distinct developmentally immature signature.
Cao et al. (2020) identified LOXL2 as a therapeutic target in cervical carcinoma where
it is positively correlated with EMT phenotype. They showed that LOXL2 silencing inhibits
the proliferation and migration of cancer cells. Panchy et al. (2019) provided insights
into the mechanistic basis of cancer cell heterogeneity and plasticity. They combined
cancer cell transcriptomics from time course data of EMT in non-tumorigenic epithelial
cells, and from epithelial cells with perturbations of key EMT factors in order to
perform an integrative analysis. They noticed a wide distribution of cancer cells
spread across the EMT spectrum, with ZEB1 playing a key role. Ramirez et al. (2020)
used a bioinformatical approach combined with mathematical modelling to analyze a
time-series of single-cell RNA-sequencing data of EMT induced cancer cell lines. They
constructed common context-specific EMT gene regulatory circuits and identified transcriptional
regulators contributing to drive or reverse EMT.
In addition to these original research contributions, the collection of articles also
included comprehensive research articles on various axes of plasticity. Kong et al.
presented an overall picture of cellular plasticity mediated by the MAPK, PI3K, STAT3,
Wnt, Hedgehog, and Notch pathways during breast cancer progression. Drapela et al.
discussed the role of ZEB1, a key EMT-inducing transcription factor involved in cell
plasticity, response to DNA damage, and in enabling resistance to various therapies.
Similarly, Sundararajan et al. (2019) reviewed the roles of GRHL2, an evolutionarily
conserved regulator of the epithelial phenotype. Sterneck et al. investigated the
respective roles of SLUG, a mediator of partial EMT, and E-cadherin. Zhan et al. (2019)
reviewed the role of Asporin in various cancers including breast, colorectal, and
pancreatic cancer, where it modulates the EMT transition and hence the migration and
invasiveness of tumor cells. After reviewing the increasing amount of evidence for
the significance of partial EMT states, Bhatia et al. also discussed clinical developments
in targeting epithelial-mesenchymal plasticity (EMP). Clinical and therapeutic implicates
of EMP are becoming increasingly crucial, thus indicating that the therapeutic window
in the context of EMP needs to be investigated carefully. One proposed idea can be
to ‘fix the cells’ on their position of the EMP axis, which may be possible by breaking
feedback loops embedded in a cancer cell circuitry (Williams et al., 2019; Hari et
al., 2020). Another recent approach can be re-differentiation of cancer cells into
normal epithelial cells. Recent approaches include the forced trans-differentiation
of EMT-derived breast cancer cells to being adipocytes (Ishay-Ronen et al., 2019).
Beyond EMP, plasticity along the axes of cancer cell stemness was discussed by Thankamony
et al. and plasticity along neuroendocrine prostate cancer was highlighted by Tiwari
et al. The association of tumor plasticity with senescence-associated pro-inflammatory
cytokines was reviewed by Vernot et al. and with mitochondrial involvement was discussed
by Denisenko et al. (2019). Finally, non-cell-autonomous mechanisms of cell plasticity
i.e., tumor-host interactions, were reflected upon by Mu et al. (2019) focusing on
mechanisms related to pancreatic cancer progression. The increasing realization of
the plasticity of the TME and especially of its immune components is one of the critical
topics ripe for future investigations. We hope you enjoy this series of articles and
recognize that the concept of cell plasticity is engendering a revolution in how we
think about cancer and how we might be able to create robust interventional strategies.
Author Contributions
ST and MJ conceived, wrote, and edited the final version of this editorial. SM and
HL edited and approved the final version of this editorial.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.