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Activation of the tyrosine kinase c-Src promotes breast cancer progression and poor outcomes, yet the underlying mechanisms are incompletely understood. Here, we have shown that deletion of c-Src in a genetically engineered model mimicking the luminal B molecular subtype of breast cancer abrogated the activity of forkhead box M1 (FOXM1), a master transcriptional regulator of the cell cycle. We determined that c-Src phosphorylated FOXM1 on 2 tyrosine residues to stimulate its nuclear localization and target gene expression. These included key regulators of G2/M cell-cycle progression as well as c-Src itself, forming a positive feedback loop that drove proliferation in genetically engineered and patient-derived models of luminal B-like breast cancer. Using genetic approaches and small molecules that destabilize the FOXM1 protein, we found that targeting this mechanism induced G2/M cell-cycle arrest and apoptosis, blocked tumor progression, and impaired metastasis. We identified a positive correlation between FOXM1 and c-Src expression in human breast cancer and show that the expression of FOXM1 target genes predicts poor outcomes and associates with the luminal B subtype, which responds poorly to currently approved therapies. These findings revealed a regulatory network centered on c-Src and FOXM1 that is a targetable vulnerability in aggressive luminal breast cancers.

Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence. Osteopontin promotes tumor cell proliferation, recruits macrophages, and synergizes with IL-4 to further polarize them into a pro-tumorigenic state. Macrophage depletion and osteopontin inhibition decrease recurrent tumor growth. Furthermore, targeting osteopontin in primary tumor-bearing female mice prevents metastasis, permits T cell infiltration and activation, and improves anti-PD-1 immunotherapy response. Clinically, osteopontin expression is higher in recurrent metastatic tumors versus female patient-matched primary breast tumors. Osteopontin positively correlates with macrophage infiltration, increases with higher tumor grade, and its elevated pathway activity is associated with poor prognosis and long-term recurrence. Our findings suggest clinical implications and an alternative therapeutic strategy based on osteopontin’s multiaxial role in breast cancer progression and recurrence. Osteopontin promotes tumor growth in several cancer types. Here, in a preclinical model recapitulating features of human breast cancer recurrence, the authors report that osteopontin promotes the recruitment of immunosuppressive macrophages and its targeting reduces breast tumor growth and metastasis.

Onion thrips (Thrips tabaci) can pose a significant threat to onion crops, causing leaf damage, reduced bulb size and quality, and yield loss during severe infestations. Conventional insecticide use has been the primary method for managing this pest species, but the efficacy of this approach is inconsistent. Furthermore, emerging pest resistance is a growing concern in some regions. This two-year field study aimed to assess the effectiveness of several pest management strategies in controlling onion thrips populations and limiting their impact on onion yields. The strategies tested consisted of habitat manipulations (including flower strips and straw mulch), biological control agents (Stratiolaelaps scimitus, Neoseiulus cucumeris, Amblyseius swirskii, and Beauveria bassiana), as well as physical barrier control methods (exclusion nets, kaolin, and mineral oil). Habitat manipulation techniques, particularly the use of flower strips, reduced thrips populations by up to 50% and increased onion yields by 25%. In contrast, exclusion nets had a detrimental effect on onion yields, and the other alternative control methods produced results comparable to those obtained for untreated controls. When used alone, biological control agents were not effective at maintaining thrips populations below economically damaging levels. This study offers valuable insights into effective and sustainable pest management practices for the onion industry.

Autophagy selectively targets cargo for degradation, yet mechanistic understanding remains incomplete. The ATG8-family plays key roles in autophagic cargo recruitment. Here by mapping the proximal interactome of ATG8-paralogs, LC3B and LC3C, we uncover a LC3C-Endocytic-Associated-Pathway (LEAP) that selectively recruits plasma-membrane (PM) cargo to autophagosomes. We show that LC3C localizes to peripheral endosomes and engages proteins that traffic between PM, endosomes and autophagosomes, including the SNARE-VAMP3 and ATG9, a transmembrane protein essential for autophagy. We establish that endocytic LC3C binds cargo internalized from the PM, including the Met receptor tyrosine kinase and transferrin receptor, and is necessary for their recruitment into ATG9 vesicles targeted to sites of autophagosome initiation. Structure-function analysis identified that LC3C-endocytic localization and engagement with PM-cargo requires the extended carboxy-tail unique to LC3C, the TBK1 kinase, and TBK1-phosphosites on LC3C. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signalling with autophagic degradation. Autophagy can selectively target cargo for degradation. Here the authors map the proximal interactome of ATG8-paralogs LC3B and LC3C uncovering an LC3C-Endocytic-Associated-Pathway that selectively recruits internalized plasma membrane cargo, Met and transferrin receptors, to nascent autophagosomes.

This article examines the colonial legacies shaping current language requirements for immigrants applying for settlement or citizenship in Britain. The article argues that common sense understandings of ‘national language’ and monolingualism/multilingualism were developed in the context of imperial expansion, the legacies of which resonate today in a disdain for multilingualism and other Englishes conceived as hampering cohesion. Put simply, other languages and other English are spoken here because English was there. Drawing on interviews with applicants and English teaching professionals, the article discusses how participants variously experience English language requirements. The analysis shows how the colonial legacies supporting the rise of English as a ‘world language’ cast it as the locus of a regime of audibility that establishes a hierarchy between ‘the English’ and the ‘anglicised’. In today’s Britain, the multilingualism of the other is not external and prior to Britain, but rather speaks volumes to and about contemporary Britain.

Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1 ) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data suggests that the functionality of the E2F pathway may reflect to some extent OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) strongly correlate with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels. Triple negative breast cancer is a deadly form of breast cancer with limited therapeutic options. Here the authors show the efficacy of GLUT1 pharmacological inhibition against a subset of tumors expressing RB1, thereby identifying RB1 protein level as a biomarker of sensitivity to anti-GLUT1 therapy.

This afterword addresses four broad questions raised by this special issue: uncertainty as a mode of governance, the ontological politics of naturalisation, the citizennoncitizen distinction, and performative (anxious) states. First, taking uncertainty as a mode of neoliberal governance as the starting point of analysis, this afterword invites the scrutiny of the ways in which the artifice and uncertainty of citizenship are concealed or rendered irrelevant in naturalisation processes. Second, the contributions to this special issue consider naturalisation as a social and political process, rather than solely as a legal status. Pushing this conception further, this afterword considers naturalisation as transactional in two ways: on the one hand, migrants navigate a number of formal and informal requirements and ‘tests’, where some transactions are needed along the way, be they financial, practical, or symbolic. On the other hand, transactions will also occur in the translation of political ideology into policy. Third, naturalisation regimes both blur and reify the citizen-noncitizen and the citizen-migrant distinctions. Distinctions which this afterword unpacks by unravelling the assumed separation between citizenship and migration. How are citizens and migrants migratised? How are migrants and citizens citizenised? Fourth, a further element of the analysis concerns how state-citizen relations are enacted and by extension, how the state itself is ‘made up’ and ‘anxious’. The affective politics of ‘anxious states’ are telling of the frames of desire of naturalisation, which are founded on a threefold principle: the desirability of citizenship, the desire for desirable citizens, and the desirability of the state itself.

The molecular mechanism underlying the metabolic reprogramming associated with obesity and high blood cholesterol levels is poorly understood. We previously reported that cholesterol is an endogenous ligand of the estrogen-related receptor alpha (ERRα). Using functional assays, metabolomics, and genomics, here we show that exogenous cholesterol alters the metabolic pathways in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) cells, and that this involves increased oxidative phosphorylation (OXPHOS) and TCA cycle intermediate levels. In addition, cholesterol augments aerobic glycolysis in TNBC cells although it remains unaltered in ER+ cells. Interestingly, cholesterol does not alter the metabolite levels of glutaminolysis, one-carbon metabolism, or the pentose phosphate pathway, but increases the NADPH levels and cellular proliferation, in both cell types. Importantly, we show that the above cholesterol-induced modulations of the metabolic pathways in breast cancer cells are mediated via ERRα. Furthermore, analysis of the ERRα metabolic gene signature of basal-like breast tumours of overweight/obese versus lean patients, using the GEO database, shows that obesity may modulate ERRα gene signature in a manner consistent with our in vitro findings with exogenous cholesterol. Given the close link between high cholesterol levels and obesity, our findings provide a mechanistic explanation for the association between cholesterol/obesity and metabolic reprogramming in breast cancer patients.

Dense and aligned Collagen I fibers are associated with collective cancer invasion led by protrusive tumor cells, leader cells. In some breast tumors, a population of cancer cells (basal-like cells) maintain several epithelial characteristics and express the myoepithelial/basal cell marker Keratin 14 (K14). Emergence of leader cells and K14 expression are regarded as interconnected events triggered by Collagen I, however the underlying mechanisms remain unknown. Using breast carcinoma organoids, we show that Collagen I drives a force-dependent loop, specifically in basal-like cancer cells. The feed-forward loop is centered around the mechanotransducer Yap and independent of K14 expression. Yap promotes a transcriptional program that enhances Collagen I alignment and tension, which further activates Yap. Active Yap is detected in invading breast cancer cells in patients and required for collective invasion in 3D Collagen I and in the mammary fat pad of mice. Our work uncovers an essential function for Yap in leader cell selection during collective cancer invasion. Aligned collagen I is associated with the emergence of leader cells that are responsible for collective invasion. Here, the authors show that Collagen I and Yap signalling are in a feed-forward loop to drive the collective invasion of basal-like tumour cells.

The seedcorn maggot Delia platura (Meigen), and the bean seed maggot Delia florilega (Zetterstedt) can cause considerable feeding damage to a wide range of cultivated crops. The recent discovery of two distinct genetic lines of D. platura, each with a unique distribution pattern overlapping only in eastern Canada, suggests the presence of a new cryptic species for the group. The reliable identification of the three species/lines in the seedcorn maggot complex is crucial to our understanding of their distribution, phenology, and respective contribution to crop damage as well as to the development of specific integrated pest management approaches. As these taxa are morphologically indistinguishable in the immature stages, we developed a high-resolution melting PCR (HRM) assay using primers amplifying a variable 96-bp PCR product in the CO1 mitochondrial gene for rapid and economical identification of specimens. The three species/lines exhibited distinguishable melting profiles based on their different Tm values (between 0.4 and 0.9°C) and identification results based on HRM and DNA sequencing were congruent for all specimens in the validation data set (n = 100). We then used the new, highly sensitive HRM assay to identify survey specimens from the seedcorn maggot complex collected in Quebec, Canada, between 2017 and 2019. Progress curves developed to document the temporal occurrence patterns of each species/lines indicate differences between taxa, with the N-line (BOLD:AAA3453) of D. platura appearing approximately 17 d before D. florilega (BOLD:ACR4394) and the H-line (BOLD:AAG2511) of D. platura.