The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras ...allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) > 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.
Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or ...differentiate into immune cells that contribute to disease pathology in peripheral tissues
. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin
. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.
We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as ...well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.
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•Evolution of melanoma from precursors revealed through sequencing of DNA and RNA•MAPK pathway output progressively ramps up during progression•The chromatin landscape is reconfigured at the transition to melanoma•G1/S checkpoint override coincides with transition from in situ to invasive melanoma
Shain et al. show sequential MAPK pathway activation, telomerase upregulation, chromatin landscape modulation, G1/S checkpoint override, MAPK signaling ramp-up, p53 pathway disruption, and PI3K pathway activation during the evolution from pre-malignant lesions to melanoma, but no metastasis-specific mutations.
With international arrivals surpassing 1.5 billion for the first time in 2019 the long-term evolution of tourism demonstrates prolific path dependence with a decade of growth since the global ...financial crisis. This latest period of unfettered international tourism development has come to an abrupt end as the impact of COVID-19 has brought the sector to a near standstill. As the world grapples with the realities of the global pandemic there is an opportunity to rethink exactly what tourism will look like for the decades ahead. Key concepts in evolutionary economic geography, especially path dependence/creation and institutional inertia/innovation, show variations in pathways for travel and tourism in a COVID-19 world. A path that leads to transformation in tourism can be realized if sufficient institutional innovation occurs on both the demand and supply side of tourism that can foster the emergence of new paths. COVID-19 presents a once in a generation opportunity where the institutional pump is primed for transformation. Whether that leads to a radical transformation of the tourism sector remains to be seen, but the imprint it will leave on both the demand and supply of tourism will have long-term, incremental impacts for years to come and ultimately move us closer towards the transformation of tourism.
Mitochondria and Cancer Zong, Wei-Xing; Rabinowitz, Joshua D; White, Eileen
Molecular cell,
03/2016, Volume:
61, Issue:
5
Journal Article
Peer reviewed
Open access
Decades ago, Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that ...the genetic events that drive aberrant cancer cell proliferation also alter biochemical metabolism, including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy; provide building blocks for new cells; and control redox homeostasis, oncogenic signaling, innate immunity, and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mtDNA limits tumorigenesis, and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multifunctional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.
Summary
The zygnematophycean algae occupy an important phylogenetic position as the closest living relatives of land plants. Reverse genetics is quite useful for dissecting the functions of genes. ...However, this strategy requires genetic transformation, and there are only a few reports of successful transformation in zygnematophycean algae.
Here, we established a simple and highly efficient transformation technique for the unicellular zygnematophycean alga Closterium peracerosum‐strigosum‐littorale complex using a square electric pulse‐generating electroporator without the need for cell wall removal.
Using this method, the transformation efficiency increased > 100‐fold compared with our previous study using particle bombardment. We also succeeded in performing CRISPR/Cas9‐based gene knockout using this new method.
Our method requires only small amounts of labor, time and incubator space. Moreover, our technique could also be utilized to transform other charophycean algae with available genome information by optimizing the electric pulse conditions.
Solid tumors are not simply clones of cancer cells. Instead, they are abnormal organs composed of multiple cell types and extracellular matrix. Some aspects of tumor development resemble processes ...seen in developing organs, whereas others are more akin to tissue remodeling. Some microenvironments, particularly those associated with tissue injury, are favorable for progression of mutant cells, whereas others restrict it. Cancer cells can also instruct surrounding tissues to undergo changes that promote malignancy. Understanding the complex ways in which cancer cells interact with their surroundings, both locally in the tumor organ and systemically in the body as a whole, has implications for effective cancer prevention and therapy.
The capabilities of the numerical simulation of technological processes are limited by the accuracy and efficiency of determining the properties of materials continuously changing under repeated ...heating and cooling. The parameters of structural transformations are the principal factors affecting the properties of alloyed steels. In this paper, we present a method for determining the parameters of relationships describing C-shaped curves in the experimental diagrams of isothermal decomposition of austenite. The proposed approach makes it possible to reconstruct the entire C-shaped curve using a relatively small fragment near the “nose” (based on three points). The joint processing of a series of curves provides determining the parameters of ferritic, pearlitic and bainitic transformation kinetics. However, one should take into account the distinctive features of the diffusion decomposition of austenite. For example, ferrite and pearlite are formed in overlapping temperature ranges and have similar mechanical properties, but their combining into a single ferrite-pearlitic structure complicates the construction of a mathematical model for the transformation. The bainitic transformation is a transient one between diffusion and diffusionless transformations. In a part of the transformation temperature range the limit of conversion level is a function of temperature (just as in the case of martensitic transformation). It has been shown that, for the case of ferrite-pearlitic transformation, the best results can be obtained with the use of Kolmogorov–Avrami equation, whereas for the case of bainitic transformation, the best results can be obtained with the use of Austin–Rickett equation modified to take into account an incomplete conversion level of the transformation.
It is no surprise that research on digital transformation (DT) has raised vast interest among academics in recent decades. Countries, cities, industries, companies, and people all face the same ...challenge of adapting to a digital world. The aim of the paper is twofold. First, map the thematic evolution of the DT research in the areas of business and management, because existing research in these areas to date has been limited to certain domains. To achieve this, articles were identified and reviewed that were published in the Chartered Association of Business Schools’ (ABS) ≥ 2-star journals. Based on these findings, the second objective of this paper will be to propose a synergistic framework that relates existing research on DT to the areas of business and management, which will help form the evolutionary perspective taken in this paper. Considering the emerging development of the topic under investigation, the framework is understood as a sound basis for continued discussion and forthcoming research.
•This article maps the thematic evolution of current research on digital transformation in business and management.•217 articles from leading business and management journals are analyzed using diverse methodological procedures.•A synergistic framework linking current research on digital transformation with business and management is proposed.
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