Regulation of ATP utilization during metastatic cell migration by collagen architecture

Zanotelli, Matthew R.; Goldblatt, Zachary E.; Miller, Joe; Bordeleau, François; Li, Jiahe; VanderBurgh, Jacob A.; Lampi, Marsha C.; King, Michael R.; Reinhart‐King, Cynthia A.

doi:10.1091/mbc.e17-01-0041

Cited by 142 publications

(150 citation statements)

References 69 publications

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“…Extracellular ATP has been implicated in facilitating chemotaxis of microglia, microglial activation, inflammation, and several neurological or neuropathological processes (63). Additionally, it can be internalized by tumor cells, increasing their intracellular ATP levels conferring metabolic reprogramming, increased tumor aggressivity, and treatment resistance (64)(65)(66)(67)(68). A recent lung cancer study has shown eATP to be involved in epithelial-to-mesenchymal transition, cell migration, and metastasis (69).…”

Section: Discussionmentioning

confidence: 99%

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Gupta

Vučković

Zhang

et al. 2020

Preprint

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AbstractGlioblastoma (GBM) is uniformly fatal with a one year median survival rate, despite the best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified the tumor-promoting effects of prior radiotherapy (RT) on patient-derived intracranial GBM xenografts and characterized the metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24h following 20Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p<0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from the radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (like, modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of the pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using 1H-NMR revealed significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, TCA intermediates, and increased ATP and GTP. Glutathione and ASC showed highest VIPpred (1.65) in OPLS-DA analysis. Involvement of ASC catabolism was further confirmed by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occuring 2 months vs. 24h following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, as well as elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest that IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.

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Section: Discussionmentioning

confidence: 99%

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Gupta

Vučković

Zhang

et al. 2020

Preprint

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“…Zhang et al used intracellular measurements of ATP/ADP levels during breast cancer cell invasion to show that energy levels play a role in the coordinated leader-follower cell transition during collective migration (Zhang et al, 2019). ATP/ADP levels are also proportional to the propensity of cancer cells to migrate in vitro (Zanotelli et al, 2018). Our results further strengthen the link between cell migration and ATP/ADP levels and show that dynamic changes in ATP/ADP levels are required for sustaining cell migration by regulating the duration and periodicity of the migratory and stationary phases.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy is associated with energetic stress (Kroemer et al, 2010). The energy status of cells, represented by the ATP/ADP ratio, is closely related to the ability of metastatic cancer cells to migrate in vitro (Zanotelli et al, 2018). We used a ratiometric biosensor of ATP/ADP (PercevalHR) (Tantama et al, 2013) to explore energy consumption during cell migration in vivo and to investigate the link between energy consumption and autophagy.…”

Section: Autophagy Is Induced By Bioenergetic Requirements During Celmentioning

confidence: 99%

The dynamic interplay between ATP/ADP levels and autophagy sustain neuronal migrationin vivo

Bressan

Pecora

Gagnon

et al. 2020

Preprint

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Highlights ATP/ADP levels dynamically change during cell migration  A decrease in ATP levels leads to cell pausing and autophagy induction via AMPK  Autophagy is required to sustain neuronal migration by recycling focal adhesions  Autophagy level is dynamically modulated by migration-promoting and inhibiting cues AbstractCell migration is a dynamic process that entails extensive protein synthesis and recycling, structural remodeling, and a considerable bioenergetic demand. Autophagy is one of the pathways that maintain cellular homeostasis. Time-lapse imaging of autophagosomes and ATP/ADP levels in migrating cells in the rostral migratory stream of mice revealed that decrease in ATP levels force cells into the stationary phase and induce autophagy. Genetic impairment of autophagy in neuroblasts using either inducible conditional mice or CRISPR/Cas9 gene editing decreased cell migration due to the longer duration of the stationary phase. Autophagy is modulated in response to migration-promoting and inhibiting molecular cues and is required for the recycling of focal adhesions. Our results show that autophagy and energy consumption act in concert in migrating cells to dynamically regulate the pace and periodicity of the migratory and stationary phases in order to sustain neuronal migration.

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“…For instance, blocking ROCK (Rho-associated protein kinase) can inhibit cell contractility and invasion potential of breast cancer stem cells (Srinivasan, Ashok et al 2017). At a biophysical level, TME is often characterized by increased stiffness due to ECM remodeling, increased compressive stress due to confined growth, enhanced interstitial pressure and an increased interstitial fluid flow (Zanotelli, Goldblatt et al 2018). Extrinsic mechanical forces exerted by ECM constituents can trigger biochemical changes inside cells such as cytoskeleton rearrangement, and changes in gene expression, protein-protein interactions and enzyme modifications, thus converging on various mechano-transduction and mechano-chemical axes (Ogden, Waziri et al 2008, Broders-Bondon, Nguyen Ho-Bouldoires et al 2018, Roy Choudhury, Gupta et al 2019 Cancer cells display variations in response to extrinsic biomechanical stimuli, leading to heterogeneity in their biophysical properties, which influences the overall nature of cells such as stemness and differentiation.…”

Section: Biophysical Characterization Of Cscs and Their Subsetsmentioning

confidence: 99%

Cancer Stem Cell Plasticity – A Deadly Deal

Archana¹,

Kritika²,

Murali³

et al. 2019

Preprint

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Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. The molecular mechanisms underlying such plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment. In this review, we discuss the recent developments in understanding CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity with implications in improving existing therapeutic approaches.

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Regulation of ATP utilization during metastatic cell migration by collagen architecture

Cited by 142 publications

References 69 publications

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

The dynamic interplay between ATP/ADP levels and autophagy sustain neuronal migrationin vivo

Cancer Stem Cell Plasticity – A Deadly Deal

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Regulation of ATP utilization during metastatic cell migration by collagen architecture

Cited by 142 publications

References 69 publications

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

The dynamic interplay between ATP/ADP levels and autophagy sustain neuronal migrationin vivo

Cancer Stem Cell Plasticity &ndash; A Deadly Deal

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Product

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Cancer Stem Cell Plasticity – A Deadly Deal