Therapeutic resistance continues to be an indominable foe in our ambition for curative cancer treatment. Recent insights into the molecular determinants of acquired treatment resistance in the ...clinical and experimental setting have challenged the widely held view of sequential genetic evolution as the primary cause of resistance and brought into sharp focus a range of non-genetic adaptive mechanisms. Notably, the genetic landscape of the tumour and the non-genetic mechanisms used to escape therapy are frequently linked. Remarkably, whereas some oncogenic mutations allow the cancer cells to rapidly adapt their transcriptional and/or metabolic programme to meet and survive the therapeutic pressure, other oncogenic drivers convey an inherent cellular plasticity to the cancer cell enabling lineage switching and/or the evasion of anticancer immunosurveillance. The prevalence and diverse array of non-genetic resistance mechanisms pose a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes. In this Perspective we discuss the key principles of non-genetic therapy resistance in cancer. We provide a perspective on the emerging data from clinical studies and sophisticated cancer models that have studied various non-genetic resistance pathways and highlight promising therapeutic avenues that may be used to negate and/or counteract the non-genetic adaptive pathways.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Epithelial‐to‐mesenchymal transition (EMT), a process through which epithelial tumor cells acquire mesenchymal phenotypic properties, contributes to both metastatic dissemination and therapy ...resistance in cancer. Accumulating evidence indicates that nonepithelial tumors, including melanoma, can also gain mesenchymal‐like properties that increase their metastatic propensity and decrease their sensitivity to therapy. In this review, we discuss recent findings, illustrating the striking similarities—but also knowledge gaps—between the biology of mesenchymal‐like state(s) in melanoma and mesenchymal state(s) from epithelial cancers. Based on this comparative analysis, we suggest hypothesis‐driven experimental approaches to further deepen our understanding of the EMT‐like process in melanoma and how such investigations may pave the way towards the identification of clinically relevant biomarkers for prognosis and new therapeutic strategies.
Epithelial‐to‐mesenchymal transition (EMT) allows epithelial tumor cells to acquire mesenchymal phenotypic properties to metastasize and resist drug treatment. Melanoma cells undergo a process called phenotype switching, that strikingly resembles EMT, both in phenotypic characteristics and molecular mechanisms. In this review, we highlight both similarities and differences between EMT and phenotype switching, identifying knowledge gaps in the field and proposing experimental approaches to investigate this key phenomenon.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
In many developing countries, aquaculture is key to ensuring food security for millions of people. It is thus important to measure the full implications of environmental changes on the sustainability ...of aquaculture. We conduct a double meta-analysis (460 articles) to explore how global warming and antimicrobial resistance (AMR) impact aquaculture. We calculate a Multi-Antibiotic Resistance index (MAR) of aquaculture-related bacteria (11,274 isolates) for 40 countries, of which mostly low- and middle-income countries present high AMR levels. Here we show that aquaculture MAR indices correlate with MAR indices from human clinical bacteria, temperature and countries' climate vulnerability. We also find that infected aquatic animals present higher mortalities at warmer temperatures. Countries most vulnerable to climate change will probably face the highest AMR risks, impacting human health beyond the aquaculture sector, highlighting the need for urgent action. Sustainable solutions to minimise antibiotic use and increase system resilience are therefore needed.
Sox9 is a transcription factor expressed in most solid tumors. However, the molecular mechanisms underlying Sox9 function during tumorigenesis remain unclear. Here, using a genetic mouse model of ...basal cell carcinoma (BCC), the most frequent cancer in humans, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/β-catenin-dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog signaling completely prevents BCC formation and leads to a progressive loss of oncogene-expressing cells. Transcriptional profiling of oncogene-expressing cells with Sox9 deletion, combined with in vivo ChIP sequencing, uncovers a cancer-specific gene network regulated by Sox9 that promotes stemness, extracellular matrix deposition, and cytoskeleton remodeling while repressing epidermal differentiation. Our study identifies the molecular mechanisms regulated by Sox9 that link tumor initiation and invasion.
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•Sox9 is required for BCC formation in a Wnt/β-catenin-dependent manner•ChIP-seq and microarray reveal a Sox9-controlled cancer-specific gene network•Sox9 promotes BCC stemness and self-renewal and inhibits differentiation•Sox9 controls ECM and cytoskeleton remodeling during tumor invasion
Using mouse models of BCC, Larsimont et al. show that Sox9 is required for self-renewal of oncogene-expressing cells and BCC formation. Transcriptional profiling combined with ChIP sequencing uncovered a cancer-specific gene network regulated by Sox9 that promotes stemness, represses differentiation, and induces ECM and cytoskeleton remodeling required for tumor invasion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitochondria are critical hubs for the integration of several key metabolic processes implicated in cell growth and survival. They originated from bacterial ancestors through endosymbiosis, following ...the transfer of more than 90% of their endosymbiont genome to the host cell nucleus. Over time, a mutually beneficial symbiotic relationship has been established, which relies on continuous and elaborate signaling mechanisms between this life‐essential organelle and its host. The ability of mitochondria to signal their functional state and trigger compensatory and adaptive cellular responses has long been recognized, but the underlying molecular mechanisms involved have remained poorly understood. Recent evidence indicates that non‐coding RNAs (ncRNAs) may contribute to the synchronization of a series of essential cellular and mitochondrial biological processes, acting as “messengers” between the nucleus and the mitochondria. Here, we discuss the emerging putative roles of ncRNAs in various bidirectional signaling pathways established between the host cell and its mitochondria, and how the dysregulation of these pathways may lead to aging‐related diseases, including cancer, and offer new promising therapeutic avenues.
The crosstalk between nuclear genome activity and mitochondrial function relies on multiple mechanisms, involving signal transduction and transcriptional control. This review summarizes and reflects on how the rapidly growing pool of non‐coding RNAs contributes to this process.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. ...Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.
COP1 is an E3 ubiquitin ligase that is involved in the ubiquitylation of various protein substrates to trigger their proteasomal degradation. Although originally identified in a light signalling ...pathway in plants, biochemical studies have identified putative targets of mammalian COP1 with relevant roles in tumorigenesis, including the oncoproteins JUN and ETV family members, as well as the p53 tumour suppressor. Recent genetic studies have shown that COP1 deficiency leads to spontaneous tumour formation in mice, and have identified mutations in COP1 and its substrates in various human cancers. These findings add to our growing appreciation of the roles for E3 ligases in cancer.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the ...biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance.
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•Minimal residual diseases in melanoma exhibit cellular and spatial heterogeneity•Cell-state transition contributes to co-emergence of distinct drug-tolerant states•RXR signaling drives emergence of a cell population conferring treatment resistance•Targeting RXR signaling is promising for delaying or obviating relapse in melanoma
Drug-tolerant cells that persist through treatment of melanoma exhibit multiple transcriptional states, one of which is a key driver that can be targeted therapeutically.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Transition from proliferative‐to‐invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of ...mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down‐regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR‐depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re‐expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor‐initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient‐rich conditions by repressing translation of selected ISR RNAs.
SYNOPSIS
Long non‐coding RNA TINCR blocks the acquisition of invasive phenotypes in melanoma, including drug resistance and metastasis dissemination. TINCR targets RNAs associated with invasive phenotypes, preventing their interaction with ribosomes.
High TINCR levels prevent translational reprogramming and ATF4 translation, maintaining proliferative, epithelial‐like states.
TINCR downregulation leads to translational reprogramming and ATF4 activation, promoting invasion in nutrient‐rich conditions.
TINCR interacts with selected integrated stress response RNAs, preventing their binding to the translating ribosomes.
Long non‐coding RNA TINCR blocks the acquisition of invasive phenotypes in melanoma, including drug resistance and metastasis dissemination. TINCR targets RNAs associated with invasive phenotypes, preventing their interaction with ribosomes.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We present SCENIC, a computational method for simultaneous gene regulatory network reconstruction and cell-state identification from single-cell RNA-seq data (http://scenic.aertslab.org). On a ...compendium of single-cell data from tumors and brain, we demonstrate that cis-regulatory analysis can be exploited to guide the identification of transcription factors and cell states. SCENIC provides critical biological insights into the mechanisms driving cellular heterogeneity.