SUMMARY Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and the underlying mechanisms of, KrasG12D–independent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional co-activator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.

Plant intracellular immune receptors comprise a large number of multi-domain proteins resembling animal NOD-like receptors (NLRs). Plant NLRs typically recognize isolate-specific pathogen-derived effectors, encoded by avirulence (AVR) genes, and trigger defense responses often associated with localized host cell death. The barley MLA gene is polymorphic in nature and encodes NLRs of the coiled-coil (CC)-NB-LRR type that each detects a cognate isolate-specific effector of the barley powdery mildew fungus. We report the systematic analyses of MLA10 activity in disease resistance and cell death signaling in barley and Nicotiana benthamiana. MLA10 CC domain-triggered cell death is regulated by highly conserved motifs in the CC and the NB-ARC domains and by the C-terminal LRR of the receptor. Enforced MLA10 subcellular localization, by tagging with a nuclear localization sequence (NLS) or a nuclear export sequence (NES), shows that MLA10 activity in cell death signaling is suppressed in the nucleus but enhanced in the cytoplasm. By contrast, nuclear localized MLA10 is sufficient to mediate disease resistance against powdery mildew fungus. MLA10 retention in the cytoplasm was achieved through attachment of a glucocorticoid receptor hormone-binding domain (GR), by which we reinforced the role of cytoplasmic MLA10 in cell death signaling. Together with our data showing an essential and sufficient nuclear MLA10 activity in disease resistance, this suggests a bifurcation of MLA10-triggered cell death and disease resistance signaling in a compartment-dependent manner.

DREB transcription factors play key roles in plant stress signalling transduction pathway, they can specifically bind to DRE/CRT element (G/ACCGAC) and activate the expression of many stress inducible genes. Here, a novel rice DREB transcription factor, OsDREB1F, was cloned and characterised via subtractive suppression hybridisation (SSH) from upland rice. Expression analysis revealed that OsDREB1F gene was induced by salt, drought, cold stresses, and also ABA application, but not by pathogen, wound, and H2O2. Subcellular localization results indicated that OsDREB1F localizes in nucleus. Yeast activity assay demonstrated that OsDREB1F gene encodes a transcription activator, and can specifically bind to DRE/CRT but not to ABRE element. Transgenic plants harbouring OsDREB1F gene led to enhanced tolerance to salt, drought, and low temperature in both rice and Arabidopsis. The further characterisation of OsDREB1F-overexpressing Arabidopsis showed that, besides activating the expression of COR genes which contain DRE/CRT element in their upstream promoter regions, the expression of rd29B and RAB18 genes were also activated, suggested that OsDREB1F may also participate in ABA-dependent pathway.

Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras G12D-driven mouse model of PDAC has established a critical role for sustained Kras G12D expression in tumor maintenance, providing a model to determine the potential for, and the underlying mechanisms of, Kras G12D-independent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of Kras G12D expression and downstream

Summary Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a dismal 5-year survival rate of 8% 1 . Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in >90% of PDAC, and its signaling surrogates has yielded encouraging preclinical results with experimental agents 2 - 4 . However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies 5 , 6 . Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signaling essential for malignant transformation and tumor maintenance. Insights into the complexity of the functional surfaceome have been technologically limited until recently, and, in the case of PDAC, the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signaling remains largely unexplored. Here, we developed an unbiased, functional target discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which uncovered syndecan-1 (SDC1) as a protein upregulated at the cell surface by KRAS*. Cell surface localization of SDC1 is essential for disease maintenance and progression, where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth. Thus, our study forges a mechanistic link between KRAS* signaling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.

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By combining living anionic polymerization and hydrosilylation, densely grafted bottlebrush polymers with controlled spacing of branch points are prepared. Dimethyl(4-vinylphenyl)silane and dimethyl(4-(1-phenylvinyl)phenyl)silane are anionically (co)polymerized to synthesize uniform, alternating, and gradient in-chain silyl-hydride (Si-H) functionalized backbones. The spacing of branch points is controlled effectively by regulating the distribution of Si-H groups along the backbones. Three backbones with a similar number of Si-H groups but variable distributions are used to synthesize corresponding bottlebrush polymers via hydrosilylation between the backbones and chain-end vinyl functionalized polystyrene. The uniformly grafted bottlebrush exhibits the highest hydrodynamic radius (Rh ) of 5.6 nm and the lowest Tg of 79 °C which may be attributed to its compact grafted structure. This methodology exhibits high efficiency and convenience for the construction of bottlebrushes with controlled distribution of brushes.

Tropical cyclones (TCs), some of the most influential weather events across the globe, are modulated by the El Niño–Southern Oscillation (ENSO). However, little is known about the feedback of TCs on ENSO. Here, observational and modelling evidence shows that TC activity in the southeastern western North Pacific can affect the Niño-3.4 index 3 months later. Increased TC activity in July–September can significantly contribute to the intensity of ENSO in October–December by weakening the Walker circulation and enhancing eastward-propagating oceanic Kelvin waves in the tropical Pacific. Thus, the greater the accumulated cyclone energy, the stronger (weaker) the El Niño (La Niña). A new physics-based empirical model for ENSO is constructed that significantly outperforms current models in predicting ENSO intensity from July to December and addressing the problem about the target period slippage of ENSO. Results suggest that TCs may provide significant cross-scale feedback to ENSO.