Metastasis remains the leading cause of cancer-related mortality and is driven by pronounced tumour cell plasticity. Here we identify the transmembrane glycoprotein trophoblast cell-surface antigen 2 (TROP2) as a marker...Metastasis remains the leading cause of cancer-related mortality and is driven by pronounced tumour cell plasticity. Here we identify the transmembrane glycoprotein trophoblast cell-surface antigen 2 (TROP2) as a marker of poor-prognosis colorectal cancer (CRC) associated with WNT, fetal-like tumour cell states that are linked to metastasis and therapy resistance. Functional analyses demonstrate that TROP2 cells exhibit context-dependent stem-like capacity and the ability to initiate metastatic outgrowth. Given that these detrimental tumour states converge on the cell-surface antigen TROP2, we explored therapeutic targeting of this cell population using clinically relevant TROP2-directed antibody-drug conjugates. Time-resolved analyses reveal therapy-associated dynamics in tumour cell state composition between WNT LGR5 states and WNTTROP2 fetal-like states. Conventional chemotherapy promotes the induction of TROP2-expressing cells, whereas TROP2 antibody-drug conjugates selectively target these populations and remodel the tumour cell state landscape. Exploiting this plasticity, combined chemotherapy and TROP2 targeting enhances anti-tumour efficacy in patient-derived models. Together, our findings identify TROP2 as a therapeutic vulnerability of CRC and highlight the importance of targeting tumour cell states to improve therapeutic efficacy and overcome resistance in advanced disease.
Tsyporin J, Zhang M, Qi C
… +35 more, Segal A, Li X, Kim H, Choi SH, Pavlovic I, Bandiera S, Finn T, Kim SK, Shibata A, Nakamura T, Onishi K, Zhang Z, Hammarlund E, Su G, Salla N, Kachko J, Hawley C, Li S, Doyle DZ, Peng X, Nottoli T, Ruiz-Reig N, Tissir F, Nakagawa Y, Herzog E, Ma S, Gobeske K, Pattabiraman K, Shimogori T, Duque A, Fornito A, Huang H, Shibata M, Chen B, Sestan N
The cerebral cortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas forming distributed networks...The cerebral cortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas forming distributed networks that support abstract cognition at the other. The developmental mechanisms shaping this axis remain unclear. Here we present converging multispecies evidence supporting the multinodal induction-exclusion in network development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion driven by two opposing transcriptomically defined programs. 'Pericentral' programs are induced around the frontotemporal poles, progress inwards toward the central regions of the undifferentiated neocortex and define higher-order association features. 'Central' programs are induced centrally through first-order sensorimotor thalamocortical inputs, establish primary areas and exclude pericentral programs. These conserved programs compete for space, resulting in compartmentalized expression of axon guidance, cell-cell adhesion, retinoic acid signalling, synaptogenesis, WNT signalling and autism-risk-associated genes. Notably, PLXNC1 and SEMA7A, a receptor-ligand pair representing pericentral and central programs, respectively, exhibit repulsive interactions between primary and higher-order association corticocortical axons. Induction and exclusion together establish an S-A organization in which primary areas emerge as focal islands within a broader ocean of distributed association networks. The MIND model provides a unifying framework for experimental, evolutionary and clinical phenomena, revealing induction and exclusion as antagonistic yet complementary principles shaping the S-A axis and processing hierarchies.
Patients with colorectal cancer (CRC) frequently develop liver metastases. The prognosis of these patients is skewed by the histopathological heterogeneity of their liver metastases. Patients with 'replacement' metastase...Patients with colorectal cancer (CRC) frequently develop liver metastases. The prognosis of these patients is skewed by the histopathological heterogeneity of their liver metastases. Patients with 'replacement' metastases have a 5-year overall survival of less than 44.2%, compared with 73.4% in patients with 'encapsulated' (previously known as desmoplastic) metastases; yet there are currently no approved therapies targeting replacement liver metastases. Here we show that treatment-naive patients with CRC with liver steatosis have an increased occurrence of replacement metastases compared with patients without steatosis. Mechanistically, we find that steatosis-promoted fatty acid oxidation increases formation of replacement metastases by increasing MYC stability through acetylation. In turn, MYC activates proline synthesis, fuelling collagen production, enabling growth of replacement metastases. Targeting MYC, P5CS or COL1A1 suppresses the occurrence and growth of replacement metastases in patient-derived organoids, mouse or patient-derived xenograft models. Spatial metabolite and protein analyses of liver metastases from patients with CRC further support this mechanism. In conclusion, we provide a mechanistic understanding of the emergence of liver metastases with poor prognosis in treatment-naive patients with CRC, identifying potential targets for therapeutic intervention.
Gaggioli V, Sengupta K, Choudhury A
… +22 more, Paulson J, Kuthethur R, Bakker C, Li J, Lo CSY, Whale A, van den Berg J, Asua Intxausti L, Gil-Lanza N, Galván-Femenía I, Manolika EM, Eswaran S, Khan HN, Ferré E, Stik G, van Oudenaarden A, Papantonis A, Houseley J, Sridharan S, Chaudhuri AR, Bayona-Feliu A, Taneja N
Replication stress poses a major threat to genome integrity, yet how higher-order chromatin organization contributes to replication fork protection remains unclear. Here we show that replication stress induces the format...Replication stress poses a major threat to genome integrity, yet how higher-order chromatin organization contributes to replication fork protection remains unclear. Here we show that replication stress induces the formation of transient chromatin loops that enclose de novo heterochromatin-enriched stalled replication forks. Stressed forks preferentially stall at convergent CTCF motifs, triggering stress-dependent CTCF enrichment that constrains loop extrusion and stabilizes these structures. Loop stabilization requires both CTCF anchoring and G9a-dependent heterochromatin (trimethylation of Lys9 of histone H3 (H3K9me3)) deposition on nascent DNA within the loop body. These loops function as protective scaffolds that shield stalled and reversed forks from degradation by multiple nucleases. By contrast, combined loss of stress-induced heterochromatin and CTCF enrichment destabilizes the loop scaffold, exposing multiple entry points for nucleolytic attack and resulting in extensive nascent-strand degradation through mechanisms distinct from classical fork-reversal-dependent pathways. This protective architecture is similarly critical in BRCA2-deficient cells, in which replication-stress-associated loops predominantly safeguard replication initiation zones, while nascent DNA outside these loops undergoes massive degradation and remains highly susceptible to mutations. Our study elucidates the fundamental role of replication-stress-induced three-dimensional genome reorganization in preserving replication fork stability, thereby mitigating mutagenesis and genomic instability.
Despite huge progress accomplished in perovskite light-emitting diodes (PeLEDs), the electroluminescence performance of blue PeLEDs lags far behind, constraining the widespread application of PeLED technology for vibrant...Despite huge progress accomplished in perovskite light-emitting diodes (PeLEDs), the electroluminescence performance of blue PeLEDs lags far behind, constraining the widespread application of PeLED technology for vibrant full-colour displays. The wider bandgaps of blue emitters require higher working voltages of corresponding electroluminescent devices, intensifying the octahedral instability of perovskites with ionic nature. Here we report efficient and stable PeLEDs with saturated blue emissions by constructing hydrogen-bonding networks formed within perovskite and at the interface using isomeric molecules. The O-benzylhydroxylamine hydrochloride (OBCl) between the hole transport layer and the emitter acts as hydrogen-bonding donor, binding to the perovskite inorganic framework, which enhances the perovskite structural stability and decreases the hole energy barrier due to the large dipole moment. The isomeric N-benzylhydroxylamine hydrochloride (NBCl) added into the perovskite provides acceptor and donor sites for forming hydrogen bonding with the OB and the perovskite. The isomeric molecular hydrogen bonding reinforces the preferential orientation of perovskite films induced by OB interfacial molecules, improving the carrier mobility and further enhancing material stability. We demonstrate, as a result, blue PeLEDs with external quantum efficiencies of 16.8% at 463 nm and 22.0% at 468 nm, as well as significantly improved device stability, representing state-of-the-art performance among pure- and deep-blue PeLEDs.
Constraining the complex dynamics of the inner Earth unites research efforts across several scientific disciplines, including geochemistry, geophysics and geodynamics. Seismological and geodynamic studies offer insights...Constraining the complex dynamics of the inner Earth unites research efforts across several scientific disciplines, including geochemistry, geophysics and geodynamics. Seismological and geodynamic studies offer insights into the present state of the mantle structure, whereas geochemical approaches characterize its chemical and isotopic heterogeneities, shedding light on the complexity of its evolution. One key challenge is determining the age and origin of its chemical heterogeneities. Here we present new high-precision Nd isotopic measurements in present-day volcanism that identify heterogeneities dating back to the Earth's earliest history. We report significantly positive Nd anomalies in lavas from the submarine Fani Maoré volcano in the Comoros archipelago. These anomalies require the preservation, in the mantle, of material depleted in light rare-earth elements (REE) and formed within the first 100 million years (Myr) of Earth's history. We suggest that this material is mainly composed of bridgmanite that crystallized from an early Earth magma ocean. This Hadean bridgmanite may be more widespread in the present-day mantle than previously expected, raising new questions about its survival over billions of years of plate tectonics and vigorous mantle convection.
A major limitation on the development of a malaria vaccine is the lack of validated T cell epitope targets. Plasmodium falciparum is the most prevalent malaria parasite affecting humans in Africa, whereas Plasmodium viva...A major limitation on the development of a malaria vaccine is the lack of validated T cell epitope targets. Plasmodium falciparum is the most prevalent malaria parasite affecting humans in Africa, whereas Plasmodium vivax is more widespread and is the main species that causes malaria in the Americas and Asia. P. vivax exclusively infects peripheral-blood reticulocytes, which retain RNA and the capacity for host protein synthesis. We previously reported that reticulocytes infected with P. vivax express human leukocyte antigen class I (HLA-I), which enables recognition and killing of the parasite by CD8 T cells. Here we use immunopeptidomics to identify Plasmodium-antigen-derived peptides presented by HLA-I on infected reticulocytes. We identified 453 unique peptides, mapping to 166 proteins. Seventy-five antigens were housekeeping proteins that are constitutively expressed at multiple stages of the parasite's life cycle and are highly conserved between Plasmodium species. Identical peptides were presented in different individuals by the same or distinct HLA-A, HLA-B and HLA-C alleles, as well as by the non-classical HLA-E allele. The antigenicity of the newly identified epitopes was validated in samples from both P. vivax-infected and P. falciparum-infected individuals. Furthermore, T cell responses to several of these antigens were observed in the blood and liver of non-human primates after infection with Plasmodium or immunization with attenuated parasites. Two antigens also induced protective CD8 T cell-mediated immunity in rodents. Thus, these antigens have the potential for use in a cross-stage and cross-species malaria vaccine.
Choueiri TK, Merchan J, Patnaik A
… +23 more, Drakaki A, Rini BI, Rha SY, Lee JL, Ornstein MC, Kumar R, Hwang C, Shao Y, Park SH, Barata PC, McGregor BA, Foster P, Chen J, Eisen M, Cole H, Weeder B, Guan Y, Singh J, Kaplan A, Cho S, Markus R, Kabbarah O, McKay RR
Clear cell renal cell carcinoma (ccRCC) is largely driven by the transcription factor hypoxia-inducible factor 2α (HIF-2α). Here we show that monotherapy with casdatifan-an orally bioavailable, potent and selective HIF-2...Clear cell renal cell carcinoma (ccRCC) is largely driven by the transcription factor hypoxia-inducible factor 2α (HIF-2α). Here we show that monotherapy with casdatifan-an orally bioavailable, potent and selective HIF-2α inhibitor-produces meaningful, durable antitumour activity with manageable safety in individuals with refractory metastatic ccRCC. Dose-expansion data from the ARC-20 study ( NCT05536141 ) are presented, including for the 100 mg once daily (QD) cohort (n = 32) and the total cohort (n = 127). Treatment discontinuation from casdatifan-related adverse events was infrequent (3%), and class-effect toxicities included anaemia and hypoxia. The confirmed objective response rates (ORRs) were 35% (95% confidence intervals (CI) = 19-55%; 100 mg QD) and 31% (95% CI = 23-40%; total); median progression-free survival (PFS) was not estimable (95% CI = 5.7-not estimable; 100 mg QD) and 12.2 months (9.4-20.6; total). Greater maximal reductions in serum erythropoietin were associated with improved clinical outcomes, including a higher ORR (P = 0.001), lower rates of progressive disease (P = 0.003) and longer PFS (P = 0.006). Erythropoietin expression was restricted to cancer cells and was significantly higher at the mRNA level in patients with clinical benefit. Concordantly, HIF-2α protein expression and HIF-2α expression signature were associated with prolonged PFS. Overall, our findings show that casdatifan achieves meaningful, durable responses with manageable safety. These data establish a link between on-target HIF-2α pathway modulation, tumour biology and clinical efficacy.
Hawking radiation-the emission of quantum particles at the event horizon of a black hole-connects gravity with quantum mechanics and thermodynamics. But Hawking radiation has never been observed in astronomy, only in lab...Hawking radiation-the emission of quantum particles at the event horizon of a black hole-connects gravity with quantum mechanics and thermodynamics. But Hawking radiation has never been observed in astronomy, only in laboratory analogues, and the chances of ever observing it in space are astronomically small. The energy of Hawking radiation must come from the gravitational field around the black hole, but how field quanta generate Hawking quanta has been unknown. Here we report on experimental and theoretical evidence for the process that generates Hawking radiation in a fibre-optical analogue of the event horizon. There, as in gravity, it has been believed that Hawking radiation comes from a complicated, cascaded process; here we have identified theoretically a simple, direct process and observed experimentally how this process reacts back onto the field. Our findings suggest an equally direct process for other laboratory analogues and perhaps also for gravitational fields, shedding light on how black holes might radiate.