The two faces of the Integrated Stress Response in cancer progression and therapeutic strategies.

Abstract In recent years considerable progress has been made in identifying the impact of mRNA translation in tumour progression. Cancer cells hijack the pre-existing translation machinery to thrive under the adverse conditions originating from intrinsic oncogenic programs, that increase their energetic demand, and from the hostile microenvironment. A key translation program frequently dysregulated in cancer is the Integrated Stress Response, that reprograms translation by attenuating global protein synthesis to decrease metabolic demand while increasing translation of specific mRNAs that support survival, migration, immune escape. In this review we provide an overview of the Integrated Stress Response, emphasise its dual role during tumorigenesis and cancer progression, and highlight the therapeutic strategies available to target it

Anti-aging and neuroprotective properties of Grifola frondosa and Hericium erinaceus extracts

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/nu14204368/s1. Table S1. Analytes identified by GC/MS on the basis of match with NIST2014 library and the corresponding target ions used to quantify them. Table S2. Yeast strains used in this study. Figure S1 Calibration curve and linear regression curve for ET. Figure S2 Evaluation of interference of fungal extracts on ThT assay. Figure S3. High fungal extract concentrations are toxic for adult flies.Nutrition has relevant consequences for human health and increasing pieces of evidence indicate that medicinal mushrooms have several beneficial effects. One of the main issues in Western countries is represented by the challenges of aging and age-related diseases, such as neurodegenerative disorders. Among these, Parkinson’s disease (PD) affects 10 million people worldwide and is associated with α-synuclein misfolding, also found in other pathologies collectively called synucleinopathies. Here, we show that aqueous extracts of two edible mushrooms, Grifola frondosa and Hericium erinaceus, represent a valuable source of β-glucans and exert anti-aging effects in yeast. Their beneficial effects are mediated through the inhibition of the Ras/PKA pathway, with increased expression of heat shock proteins, along with a consistent increase of both mean and maximal lifespans. These fungal extracts also reduce the toxicity of α-synuclein heterologously expressed in yeast cells, resulting in reduced ROS levels, lower α-synuclein membrane localization, and protein aggregation. The neuroprotective activity of G. frondosa extract was also confirmed in a PD model of Drosophila melanogaster. Taken together, our data suggest the use of G. frondosa and H. erinaceus as functional food to prevent aging and age-related disorders, further supporting the neuro-healthy properties of these medicinal mushroom extracts.We acknowledge financial support from the Italian Ministry of University and Research (MUR) through grant “Dipartimenti di Eccellenza 2017” to University of Milano-Bicocca, Department of Biotechnology and Biosciences. This research was also supported by the Italian Ministry of University and Research (MUR): Dipartimenti di Eccellenza Program (2018–2022) Dept. of Biology and Biotechnology “L. Spallanzani”, and Fondo di Ricerca e Giovani (FRG, University of Pavia). M.L. was supported by a fellowship from Fondazione Umberto Veronesi. R.M. was supported by a fellowship from the Italian Ministry of University and Research (MUR)

Metamaterial architecture from a self-shaping carnivorous plant

As meticulously observed and recorded by Darwin, the leaves of the carnivorous plant Drosera capensis L. slowly fold around insects trapped on their sticky surface in order to ensure their digestion. While the biochemical signaling driving leaf closure has been associated with plant growth hormones, how mechanical forces actuate the process is still unknown. Here, we combine experimental tests of leaf mechanics with quantitative measurements of the leaf microstructure and biochemistry to demonstrate that the closure mechanism is programmed into the cellular architecture of D. capensis leaves, which converts a homogeneous biochemical signal into an asymmetric response. Inspired by the leaf closure mechanism, we devise and test a mechanical metamaterial, which curls under homogeneous mechanical stimuli. This kind of metamaterial could find possible applications as a component in soft robotics and provides an example of bio-inspired design

Anti-aging and neuroprotective roles of medicinal mushroom extracts

Nutrition has relevant consequences on human health and increasing pieces of evidence indicate that medicinal mushrooms have several beneficial effects. One of the main issues in western countries is represented by the challenges of aging and age-related diseases, such as neurodegenerative disorders. Among these, Parkinson Disease (PD) affects 10 million people worldwide and is associated to α-synuclein misfolding, also found in other pathologies collectively called synucleinopathies. Here we show that two edible mushrooms (Grifola frondosa and Hericium erinaceus) exert anti-aging effects in a yeast model of aging. The beneficial effect of these mushrooms requires the inhibition of the Ras/PKA pathway upon fungal extract treatment, with increased expression of heat shock proteins, and increased mean and maximal lifespan. These fungal extracts also reduce the toxicity of α-synuclein exogenous expression in yeast cells, resulting in reduced ROS levels, lower α-synuclein membrane localization and protein aggregation. The neuroprotective activity of G. frondosa extract was also confirmed in a PD model of Drosophila melanogaster. Together these data suggest the use of G. frondosa and H. erinaceus as functional food to prevent age-related disorder

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

The intra-tumour microenvironment generates phenotypically distinct but inter-convertible malignant cell subpopulations that fuel metastatic spread and therapeutic-resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage-survival oncogene Microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence and drug-resistance. However, how MITF is suppressed in vivo, and how MITF-low cells in tumors escape senescence is poorly understood. Here we show that microenvironmental cues, including inflammation-mediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low, AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4- high, MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with antiPD-1 immunotherapy resistance. Since we show inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation-response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity, invasion and determine therapeutic outcome

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma.

The intra-tumour microenvironment generates phenotypically distinct but inter-convertible malignant cell subpopulations that fuel metastatic spread and therapeutic-resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage-survival oncogene Microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence and drug-resistance. However, how MITF is suppressed in vivo, and how MITF-low cells in tumors escape senescence is poorly understood. Here we show that microenvironmental cues, including inflammation-mediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low, AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4- high, MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with antiPD-1 immunotherapy resistance. Since we show inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation-response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity, invasion and determine therapeutic outcome