Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic ...T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and "normal" stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8
T cells in an antigen-specific, antigen-dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralisation of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation.
Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils ...release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target.
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.
Lung cancer is the leading cause of cancer‐related death worldwide, reflecting an unfortunate combination of very high prevalence and low survival rates, as most cases are diagnosed at advanced ...stages when treatment efficacy is limited. Lung cancer comprises several disease groups with non small cell lung cancer (NSCLC) accounting for ~ 85% of cases and lung adenocarcinoma being its most frequent histological subtype. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) affect ~ 30% of lung adenocarcinomas but unlike other commonly altered proteins (EGFR and ALK, affected in ~ 14% and 7% of cases respectively), mutant KRAS remains untargetable. Therapeutic strategies that rely instead on the inhibition of mutant KRAS functional output or the targeting of mutant KRAS cellular dependencies (i.e. synthetic lethality) are an appealing alternative approach. Recent studies focused on the metabolic properties of mutant KRAS lung tumours have uncovered unique metabolic features that can potentially be exploited therapeutically. We review these findings here with a particular focus on in vivo, physiologic, mutant KRAS activity.
Lung cancer is the leading cause of cancer‐related death worldwide. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are common drivers of lung adenocarcinoma but remain a challenging therapeutic target. Recent studies demonstrated that mutant KRAS lung tumours exhibit unique metabolic features and dependencies, which can potentially be exploited to target these aggressive cancers. This review discusses these findings and their potential therapeutic implications.
Although restoration of p53 function is an attractive tumor-specific therapeutic strategy, it remains unclear whether p53 loss is required only for transition through early bottlenecks in ...tumorigenesis or also for maintenance of established tumors. To explore the efficacy of p53 reinstatement as a tumor therapy, we used a reversibly switchable p53 knockin (KI) mouse model that permits modulation of p53 status from wild-type to knockout, at will. Using the well-characterized
Eμ-myc lymphoma model, we show that p53 is spontaneously activated when restored in established
Eμ-myc lymphomas in vivo, triggering rapid apoptosis and conferring a significant increase in survival. Nonetheless, reimposition of p53 function potently selects for emergence of p53-resistant tumors through inactivation of p19
ARF
or p53. Our study provides important insights into the nature and timing of p53-activating signals in established tumors and how resistance to p53 evolves, which will aid in the optimization of p53-based tumor therapies.
Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous ...preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence‐associated lysosomal β‐galactosidase (SA‐β‐gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose‐encapsulated nanoparticles within these cells. Here, we show that galacto‐conjugation of the BCL‐2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav‐Gal), that can be preferentially activated by SA‐β‐gal activity in a wide range of cell types. Nav‐Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav‐Gal enhances the cytotoxicity of standard senescence‐inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav‐Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto‐conjugation reduces Navitoclax‐induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.
We have developed a galactose‐conjugated derivative of Navitoclax (Nav‐Gal) with a broad‐spectrum senolytic activity. We show that Nav‐Gal efficiently kills chemotherapy‐induced senescent cells in xenografts and orthotopic in vivo models of NSCLC, resulting in impaired tumour progression. Importantly, our prodrug prevents Navitoclax‐induced platelet apoptosis in human samples and murine models. In summary, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.
Plastic packaging, in the form of films, brought several advantages to the commercialization of products given its lightness and durability. It provided better ergonomics, ease of transport, ...increased shelf life, and easy handling and use. Despite that, plastic packaging is facing enormous sustainability concerns associated with the traditional practice of linear economy, combined with commonplace irresponsible handling by citizens since it is almost exclusively designed for single-use and its end-of-life (EOL) management is not planned for. To mitigate that, the circularity of plastic packaging must be more clearly studied and evaluated through approaches such as micro-level circular economy (CE) indicators. This paper focuses on the selection of relevant CE micro-indicators specifically for the plastic packaging sector among the plethora of indicators available. Relations are also established between CE micro-indicators and CE guiding principles, as well as the most prevalent Design for X (DfX) approaches, providing new insights into how these different aspects of sustainability can be linked together. Results show three micro-level indicators as the most relevant for circularity calculation in packaging, namely those termed ‘MCI’, ‘VRE’, and ‘CEIP’, because their methodology and approach address most of the CE guiding principles and DfX approaches relevant for the packaging sector. Finally, guidelines and good practices to promote circularity adoption in the plastic packaging sector are highlighted. This work can guide companies aiming to adopt CE micro-indicators in their practical implementation, overcoming the significant knowledge barrier that currently exists.
Feeling or anticipating guilt associated with consumption situations may lead consumers to adjust their behaviors to avoid those unpleasant feelings and better conform to their personal, moral, and ...social standards. The experience of guilt regarding a consumption situation is influenced by both contextual factors, including marketing communications, and personal traits, namely the individual's proneness to feel guilt related to consumption. While research has examined the influence of contextual variables on guilt, the individual predisposition to feel guilt associated with consumption has received little attention. Understanding individual consumer guilt proneness can assist managers in customizing strategies to diverse guilt responses: recognizing varying susceptibility to guilt enables personalized approaches across the consumer journey, fostering empathetic managerial actions. This understanding can significantly impact consumer satisfaction, loyalty, and the success of marketing strategies. This study conceptualizes and proposes a measure of consumer guilt proneness, the individual tendency to feel guilt regarding transgressive consumption situations. To define the conceptual domain, a literature review is complemented with a qualitative study. Five dimensions corresponding to sources of guilt (health, extravagance, social influence, misevaluation, and ethics and sustainability) create the initial pool of items. Exploratory and confirmatory factor analyses corroborate the five‐factor measurement model. The final scale demonstrates adequate convergent, discriminant, and nomological validity. Finally, the instrument is cross‐culturally validated in three countries—Portugal, Poland, and Brazil—which not only strengthens the evidence of its validity and reliability but also lends credibility to its broader application in diverse cultural environments, particularly within Western cultures.
This work investigates the interfacial adhesion of PA6/PP‐g‐MA in a thin‐walled multilayer part obtained by injection overmoulding. This process is a good solution to the need of weight reduction for ...the sustainable and economic growth of food packaging. A rigid plastic food package is a complex multilayer structure obtained from the association of polymers with different properties to achieve good barrier, environment, or thermo‐mechanical performance. The present study aims to obtain a complete understanding of the interfacial adhesion of PA6/PP‐g‐MA interface in a three‐layer PA6/sealant/PP assembly through microscopy analysis, mechanical characterization, and inter‐diffusion models. Optical microscopy, XPS, and AFM analyses showed the presence of a copolymer interphase. This layer is greatly dependent on the holding pressure applied, which revealed to be the key parameter to obtain the best results in terms of failure strength. A better interface wettability improves the inter‐diffusion distance and thus chemical grafting efficiency. Other interface improvements were achieved by the addition of EVA in the PP‐g‐MA layer. The lowest viscosity of the EVA dispersed phase has led to a fully cohesive failure due to an interface diffusion efficiency. The presence of EVA increased more than 80% of the peeling performance of the assemblies.
KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating ...mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRAS
-driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS-mutant tumor cells in culture and progression to invasive disease in vivo. Brief pharmacological inhibition of the ERBB network enhances the therapeutic benefit of MEK (mitogen-activated protein kinase kinase) inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies.
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