Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

AbstractBoth the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy—independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

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Tumor cell plasticity, heterogeneity and resistance in crucial microenvironmental niches in glioma

10.21203/rs.3.rs-39208/v1 ◽

2020 ◽

Author(s):

Erik Jung ◽

Matthias Osswald ◽

Miriam Ratliff ◽

Ruifan Xie ◽

Sophie Weil ◽

...

Keyword(s):

Tumor Cell ◽

Cell Fate ◽

Cell Plasticity ◽

Cytotoxic Effects ◽

Perivascular Niche ◽

Tumor Cell Plasticity ◽

Preferential Location ◽

Specific Contribution ◽

Live Mouse

Abstract Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches could be determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitated resistance against cytotoxic effects of radiotherapy and chemotherapy - independently of each other, but with additive effects. Perivascular glioblastoma cells were particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depended on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induced resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

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Faculty Opinions recommendation of Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1063739.793517000 ◽

2016 ◽

Author(s):

Victoria Sanz-Moreno

Keyword(s):

Tumor Cell ◽

Cell Plasticity ◽

Tumor Cell Plasticity

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Faculty Opinions recommendation of Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1063739.516661 ◽

2007 ◽

Author(s):

Christopher Marshall

Keyword(s):

Tumor Cell ◽

Cell Plasticity ◽

Tumor Cell Plasticity

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A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate

NAR Cancer ◽

10.1093/narcan/zcab032 ◽

2021 ◽

Vol 3 (3) ◽

Author(s):

Mounira Chalabi-Dchar ◽

Tanguy Fenouil ◽

Christelle Machon ◽

Anne Vincent ◽

Frédéric Catez ◽

...

Keyword(s):

Cell Fate ◽

Ribosomal Rna ◽

Mode Of Action ◽

Rna Modifications ◽

Cell Plasticity ◽

Historical Knowledge ◽

Cytotoxic Effects ◽

Translational Activity ◽

Pancreatic Cancers ◽

Patients Experience

Abstract 5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by altering DNA metabolism. However, 5-FU mode of action is more complex than previously anticipated since 5-FU is an extrinsic source of RNA modifications through its ability to be incorporated into most classes of RNA. In particular, a recent report highlighted that, by its integration into the most abundant RNA, namely ribosomal RNA (rRNA), 5-FU creates fluorinated active ribosomes and induces translational reprogramming. Here, we review the historical knowledge of 5-FU mode of action and discuss progress in the field of 5-FU-induced RNA modifications. The case of rRNA, the essential component of ribosome and translational activity, and the plasticity of which was recently associated with cancer, is highlighted. We propose that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and ultimately to relapse.

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Cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT): Tumor cell plasticity challenges immunotherapy

Tumor Immunology and Immunotherapy ◽

10.1093/med/9780199676866.003.0027 ◽

2014 ◽

pp. 401-414

Author(s):

Tarik Regad ◽

Morgan G Mathieu

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Cell ◽

Epithelial To Mesenchymal Transition ◽

Cell Plasticity ◽

Mesenchymal Transition ◽

Tumor Cell Plasticity

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The Intimate Relationship among EMT, MET and TME: A T(ransdifferentiation) E(nhancing) M(ix) to Be Exploited for Therapeutic Purposes

Cancers ◽

10.3390/cancers12123674 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3674 ◽

Cited By ~ 1

Author(s):

Ralf Hass ◽

Juliane von der Ohe ◽

Hendrik Ungefroren

Keyword(s):

Stem Cell ◽

Phenotypic Plasticity ◽

Tumor Cell ◽

Epithelial Mesenchymal Transition ◽

Resistance Mechanisms ◽

Current Evidence ◽

Cell Plasticity ◽

New Paradigm ◽

Mesenchymal Transition ◽

Tumor Cell Plasticity

Intratumoral heterogeneity is considered the major cause of drug unresponsiveness in cancer and accumulating evidence implicates non-mutational resistance mechanisms rather than genetic mutations in its development. These non-mutational processes are largely driven by phenotypic plasticity, which is defined as the ability of a cell to reprogram and change its identity (phenotype switching). Tumor cell plasticity is characterized by the reactivation of developmental programs that are closely correlated with the acquisition of cancer stem cell properties and an enhanced potential for retrodifferentiation or transdifferentiation. A well-studied mechanism of phenotypic plasticity is the epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and clues from the tumor microenvironment in cell reprogramming. A deeper understanding of the connections between stem cell, epithelial–mesenchymal, and tumor-associated reprogramming events is crucial to develop novel therapies that mitigate cell plasticity and minimize the evolution of tumor heterogeneity, and hence drug resistance. Alternatively, vulnerabilities exposed by tumor cells when residing in a plastic or stem-like state may be exploited therapeutically, i.e., by converting them into less aggressive or even postmitotic cells. Tumor cell plasticity thus presents a new paradigm for understanding a cancer’s resistance to therapy and deciphering its underlying mechanisms.

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