Phenotypic Heterogeneity in Tumor Progression, and Its Possible Role in the Onset of Cancer

Deshmukh, Saniya; Saini, Supreet

doi:10.3389/fgene.2020.604528

Cited by 17 publications

(6 citation statements)

References 215 publications

(212 reference statements)

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“…Cancer cell plasticity increases tumor heterogeneity, facilitates metastasis formation, and often hinders treatment approaches (Deshmukh and Saini, 2020). We formulated a mathematical model of plastic phenotype transitions that result in a stable and heterogeneous phenotype distribution, mainly determined by the bias of phenotype transitions.…”

Section: Discussionmentioning

confidence: 99%

Understanding and leveraging phenotypic plasticity during metastasis formation

Shah

Philipp

Sebens

et al. 2022

Preprint

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Cancer metastasis is the primary cause of poor prognosis and cancer-related fatalities. Metastasis formation has long been identified as a process of the detrimental systemic spread of cancer, yet cure remains a challenge. Successful metastasis formation requires tumor cells to be proliferative and invasive; however, cells cannot be effective at both tasks at the same time. Tumor cells compensate for this trade-off by changing their phenotype during metastasis formation through phenotypic plasticity. Phenotypic plasticity is a cell's ability to adopt different phenotypes stochastically or driven by environmental cues. Given the different selection pressures and competitive interactions that tumor cells face in their microenvironment, it is poorly understood how plasticity shapes the process of metastasis formation. Here, we develop an ecology-inspired mathematical model that captures stochastic phenotypic plasticity and accounts for resource competition between phenotypes. We find that phenotypically plastic tumor cell populations can drive cancer metastasis. Additionally, these populations have a stable phenotype equilibrium that maintains tumor cell heterogeneity. By modeling treatment types inspired from chemo- and immunotherapy, we also highlight that phenotypically plastic populations are protected against interventions. Turning this strength into a weakness, we corroborate current clinical practices to use this plasticity as a target for adjuvant therapy. By providing a quantitative description of a phenotypically plastic cell population and its response to interventions, we can thus achieve a better mechanistic understanding of tumor cell biology and its consequences for metastasis formation.

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Section: Discussionmentioning

confidence: 99%

Understanding and leveraging phenotypic plasticity during metastasis formation

Shah

Philipp

Sebens

et al. 2022

Preprint

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“…We anticipate that the insights gained into bacterial phenotypic heterogeneity using these emergent single-cell techniques will also prove informative to relevant eukaryotic systems such as cancer. Many of the same principles governing bacterial persistence can be applied to parallel investigations into cancer persister cells; on the other hand, breakthroughs in eukaryotic single-cell technologies can accelerate the development of finer-resolution tools for prokaryotes [157][158][159]. There is a clear mutual benefit to advancing these seemingly distinct fields of research.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Technologies to Study Phenotypic Heterogeneity and Bacterial Persisters

et al. 2021

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Antibiotic persistence is a phenomenon in which rare cells of a clonal bacterial population can survive antibiotic doses that kill their kin, even though the entire population is genetically susceptible. With antibiotic treatment failure on the rise, there is growing interest in understanding the molecular mechanisms underlying bacterial phenotypic heterogeneity and antibiotic persistence. However, elucidating these rare cell states can be technically challenging. The advent of single-cell techniques has enabled us to observe and quantitatively investigate individual cells in complex, phenotypically heterogeneous populations. In this review, we will discuss current technologies for studying persister phenotypes, including fluorescent tags and biosensors used to elucidate cellular processes; advances in flow cytometry, mass spectrometry, Raman spectroscopy, and microfluidics that contribute high-throughput and high-content information; and next-generation sequencing for powerful insights into genetic and transcriptomic programs. We will further discuss existing knowledge gaps, cutting-edge technologies that can address them, and how advances in single-cell microbiology can potentially improve infectious disease treatment outcomes.

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“…Spatial heterogeneity is an essential aspect of the TME, typically involving biochemical (e.g., oxygen concentration) and biomechanical (e.g., substrate stiffness) variations. TME spatial heterogeneity results in different cellular phenotypes throughout the tumor (72). Traditionally, clones of genetic mutations have been accepted as the cause of intratumoral phenotypic heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic melanoma heterogeneity is regulated through cell-matrix interaction-dependent changes in tumor microarchitecture

Spoerri

Tonnessen-Murray

Gunasingh

et al. 2020

Preprint

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Phenotypic and functional cancer cell heterogeneity limits the efficacy of targeted and immuno-therapies. The transcription factor MITF is known to regulate melanoma cell plasticity and, consequently, response to drugs. However, the underlying mechanisms of this phenomenon remain incompletely understood. Here, we show that MITF levels control functional melanoma cell heterogeneity by fine-tuning the ability to contract the extracellular matrix, the maturation of focal adhesions and ROCK-mediated melanoma cell contractility.Modulation of MITF expression alters extracellular matrix organization, melanoma cell morphology and solid stress in three-dimensional melanoma spheroids, thereby accounting for spatial differences in cell cycle dynamics. Together, our data identify MITF as a master regulator of the melanoma micro-architecture and point towards novel targeting strategies for cancer cell heterogeneity.Significance. Development of drug resistance is a major cause of melanoma therapy failure.The role of MITF in melanoma response to therapy has been discussed controversially, which can be explained, at least in part, through the rheostat model linking MITF activity to cell proliferation. Heterogeneity is widely associated with therapy resistance, however, whether cell phenotype switching, mediated by MITF, is responsible for treatment resistance is not known. Our findings provide an in-depth mechanistic understanding of the MITF-mediated regulation of cell cycle behavior and physical regulation of the tumor architecture. As MITF is not amenable to direct drug targeting, the identification of mediators of MITF-triggered functional heterogeneity reveals novel targets that can be deployed to control this phenomenon.

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Phenotypic Heterogeneity in Tumor Progression, and Its Possible Role in the Onset of Cancer

Cited by 17 publications

References 215 publications

Understanding and leveraging phenotypic plasticity during metastasis formation

Understanding and leveraging phenotypic plasticity during metastasis formation

Single-Cell Technologies to Study Phenotypic Heterogeneity and Bacterial Persisters

Phenotypic melanoma heterogeneity is regulated through cell-matrix interaction-dependent changes in tumor microarchitecture

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