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Deletion of Twist or Snail, two key transcription factors that induce epithelial-to-mesenchymal transition in a mouse model of pancreatic ductal adenocarcinoma leads to an increase in cell proliferation, and a greater sensitivity to the chemotherapeutic agent gemcitabine, with no effect on invasion or metastasis. No requirement for EMT in metastasis It has been suggested that epithelial-to-mesenchymal transition (EMT), in which epithelial cells depolarize and adopt a fibroblast-like morphology, is a requirement for metastasis to occur. Other studies imply that the importance of EMT relies on cell-culture-based manipulation of EMT regulators. In this issue of Nature , two groups present results that suggest that EMT is not a prerequisite for metasasis. Dingcheng Gao and colleagues trace the fate of cells that have undergone EMT in mouse model for breast-to-lung metastasis. They find that although some cells undergo EMT in a primary epithelial tumour, the lung metastases mainly contain cells that have not undergone EMT. However, cells that have undergone EMT appear more resistant to chemotherapy. A microRNA that targets key EMT regulators is shown not to affect metastasis, but to reduce survival of EMT cells following chemotherapy. Raghu Kalluri and colleagues delete Twist or Snail — transcription factors that induce EMT — in a mouse model for pancreatic ductal adenocarcinoma. This leads to an increase in cell proliferation, and a greater sensitivity to chemotherapeutic agent gemcitabine, with no effect on invasion and metastasis. Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis despite current best therapies; therefore new treatment strategies are urgently required. Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of PDAC 1 , 2 , 3 , 4 . EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like cells in cell culture conditions, although such defined mesenchymal conversion (with spindle-shaped morphology) of epithelial cells in vivo is rare, with quasi-mesenchymal phenotypes occasionally observed in the tumour (partial EMT) 5 , 6 . Most studies exploring the functional role of EMT in tumours have depended on cell-culture-induced loss-of-function and gain-of-function experiments involving EMT-inducing transcription factors such as Twist, Snail and Zeb1 (refs 2 , 3 , 7 , 8 , 9 , 10 ). Therefore, the functional contribution of EMT to invasion and metastasis remains unclear 4 , 6 , and genetically engineered mouse models to address a causal connection are lacking. Here we functionally probe the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT. EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis. Suppression of EMT leads to an increase in cancer cell proliferation with enhanced expression of nucleoside transporters in tumours, contributing to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice. Collectively, our study suggests that Snail- or Twist-induced EMT is not rate-limiting for invasion and metastasis, but highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer.

Chronic fibrosis replaces functional organ tissue with scar tissue by overproduction of a thick and stiff extracellular matrix. Bladder fibrosis decreases bladder compliance, ultimately resulting in overactive bladder. The phenoconversion of fibroblasts into myofibroblasts is the defining feature of fibrosis. Recently, regionally distinct populations of bladder platelet-derived growth factor receptor alpha positive (PDGFRα + ) cells were identified as fibroblasts. Because of this heterogeneity, the identity of the bladder fibroblast cells that undergo phenotypic conversion into myofibroblasts is not clear. The current study utilized cyclophosphamide (CYP)-induced bladder inflammation to identify and characterize bladder PDGFRα + cells that become myofibroblasts. We found that suburothelial PDGFRα + cells and detrusor PDGFRα + cells display different gene expression profiles. Suburothelial PDGFRα + cells are more abundant than detrusor PDGFRα + cells and express higher levels of fibrosis-related genes. CYP-treatment increased the number of suburothelial PDGFRα + cells, increased Pdgfra, Col1a1, and Fn1 transcription in suburothelial PDGFRα + cells, and increased α-smooth muscle actin, collagen, and fibronectin protein expression. CYP-treatment likely activated TNF-α and TGF-ß pathways, as indicated by nuclear translocation of SMAD2, SMAD3, and NFκB. In conclusion, we identify suburothelial PDGFRα + cells as the fibroblast population which convert into myofibroblasts via activation of TNF-α and TGF-ß signaling pathways, due to bladder inflammation.

Tumor-derived extracellular vesicles (EVs) show great potential as biomarkers for several diseases, including pancreatic cancer, due to their roles in cancer development and progression. However, the challenge of utilizing EVs as biomarkers lies in their inherent heterogeneity in terms of size and concentration, making accurate quantification difficult, which is highly dependent on the isolation and quantification methods used. In our study, we compared three EV isolation techniques and two EV quantification methods. We observed variations in EV concentration, with approximately 1.5-fold differences depending on the quantification method used. Interestingly, all EV isolation techniques consistently yielded similar EV quantities, overall size distribution, and modal sizes. In contrast, we found a notable increase in total EV amounts in samples from pancreatic cancer cell lines, mouse models, and patient plasma, compared to non-cancerous conditions. Moreover, individual tumor-derived EVs exhibited at least a 3-fold increase in several EV biomarkers. Our data, obtained from EVs isolated using various techniques and quantified through different methods, as well as originating from various pancreatic cancer models, suggests that EV profiling holds promise for the identification of unique and cancer-specific biomarkers in pancreatic cancer.

Background Frontal sinus injuries are relatively rare among facial bone traumas. Without proper treatment, they can lead to fatal intracranial complications, including meningitis or brain abscesses, as well as aesthetic and functional sequelae. The management of frontal sinus injuries remains controversial, with various treatment methods and outcomes being reported. This article describes the clinical characteristics, surgical methods, and outcomes among 17 patients who underwent surgery for frontal sinus injury and related complications. Case presentation We retrospectively included 17 patients who underwent surgery for frontal sinus injury and its related complications at the Kangwon National University Hospital between July 2010 and September 2021. Among them, six underwent simple open reduction and fixation of the anterior wall, eight underwent sinus obliteration, and three underwent cranialization. Two patients who underwent sinus obliteration died due to infection-related complications. The patient who underwent cranialization reported experiencing chronic headache and expressed dissatisfaction regarding the esthetic outcomes of the forehead. Except for these three patients, the other patients achieved satisfactory esthetic and functional recovery. Conclusion Active surgical management of frontal sinus injuries is often required owing to the various complications caused by these injuries; however, several factors, including the fracture type, clinical presentation, related craniomaxillofacial injury, and medical history, should be considered while formulating the treatment plan. Surgical treatment through the opening of the frontal sinus should be actively considered in patients with severely damaged posterior wall fractures and those at risk of developing infection.

Vascular network density determines the amount of oxygen and nutrients delivered to host tissues, but how the vast diversity of densities is generated is unknown. Reiterations of endothelial-tip-cell selection, sprout extension and anastomosis are the basis for vascular network generation, a process governed by the VEGF/Notch feedback loop. Here, we find that temporal regulation of this feedback loop, a previously unexplored dimension, is the key mechanism to determine vascular density. Iterating between computational modeling and in vivo live imaging, we demonstrate that the rate of tip-cell selection determines the length of linear sprout extension at the expense of branching, dictating network density. We provide the first example of a host tissue-derived signal (Semaphorin3E-Plexin-D1) that accelerates tip cell selection rate, yielding a dense network. We propose that temporal regulation of this critical, iterative aspect of network formation could be a general mechanism, and additional temporal regulators may exist to sculpt vascular topology. Many animals have a network of blood vessels that supplies oxygen and nutrients to every part of the body. Each organ contains a unique pattern of blood vessels; some have lots of densely packed vessels, while others have fewer vessels that are more widely spaced. New blood vessels typically form by sprouting from the side of pre-existing vessels. This involves the endothelial cells that line the inner wall of blood vessels moving outwards to create a sprout that is made up of ‘tip cells’ and ‘stalk cells’. Tip cells are found at the front of the growing vessels and encourage the formation of new sprouts, while the stalk cells trail behind and elongate the sprout. Two signaling pathways that involve two proteins called VEGF and Notch interact with each other to control which cells become tip cells and which become stalk cells. Cells with higher levels of VEGF signaling will become tip cells. These cells also activate Notch signaling, which in turn blocks VEGF signaling in their neighboring cells. This feedback mechanism enables a new sprout to form by forcing cells present around a newly formed tip cell to become stalk cells. However, it was still not understood how the different organs develop blood vessel networks with different densities. In 2011, researchers revealed that two other proteins, Semaphorin3E and its receptor Plexin-D1, are expressed in tip cells in the back of the eye in mice and control the VEGF/Notch signaling pathway. Now Kur et al. – including some of the researchers involved in the 2011 work – have used a combination of predictive computer simulations and experimental approaches to understand this interaction in more detail. The analysis showed that Semaphorin3E and Plexin-D1 speed up VEGF/Notch signaling, which causes new tip cells to form at a faster rate, and results in a more densely packed network of blood vessels. For example, in mice that lack Semaphorin3E and Plexin-D1, VEGF/Notch signaling was slower and new tip cells formed more slowly, which resulted in the blood vessel network at the back of the mice’s eyes being less dense. Kur et al. propose that different organs have different ‘molecular metronomes’ that control the pace of VEGF/Notch signaling. A fast acting metronome would yield a dense network, while a slower one would form a less dense network. This helps to explain how diverse densities of blood vessel networks are formed in different organs. This work may aid efforts to develop therapeutic approaches for controlling the development of new blood vessels in cancers and other diseases.

Substitutional atomic doping of transition metal dichalcogenides (TMDs) in the chemical vapor deposition (CVD) process is a promising and effective strategy for modifying their physicochemical properties. However, the conventional CVD method only allows narrow-range modulation of the dopant concentration owing to the low reactivity of the precursors. Moreover, the growth of wafer-scale monolayer TMD films with high dopant concentrations is much more challenging. Herein, we report a facile doping approach based on liquid precursor-mediated CVD process for achieving high vanadium (V) doping in the MoS 2 lattice with excellent doping uniformity and stability. The lateral growth of the host MoS 2 lattice and the reactivity of the V precursor were simultaneously improved by introducing an alkali metal halide as a reaction promoter. The metal halide promoter enabled the wafer-scale synthesis of V-incorporated MoS 2 monolayer film with excessively high doping concentrations. The excellent wafer-scale uniformity of the highly V-doped MoS 2 film was confirmed through a series of microscopic, spectroscopic, and electrical analyses.

Acute intracranial subdural hematomas (SDHs) of tentorial type generally pose no serious clinical threats, and unlike other variants of SDH, rarely require surgical intervention. Herein, we present an exceedingly rare case of tentorial SDH, marked by gradual enlargement and eventually calling for surgical evacuation. A 55-year-old man presented to the emergency department after sustaining head trauma. Initially, he was alert, fully oriented, and neurologically stable. Although computed tomography (CT) of the brain revealed an acute SDH scantily distributed along right tentorium, brain swelling or midline shift was negligible. On the following day, he became confused, but pupil size and light reflex remained normal. A follow-up CT scan showed considerable enlargement of the acute SDH, with midline shift. In a matter of hours, he deteriorated to a stuporous state, as the SDH enlarged even more. We performed a craniotomy and completely evacuated the SDH on an emergency basis. As a result, the midline shift improved, and he again became alert, soon recovering without any new neurologic deficit. This illustrative case demonstrates that even a tentorial SDH may ultimately deteriorate, forcing surgical evacuation. We, therefore, feel that close observation is mandatory for such events, even if the initial volume is small.

The subpopulations of tumor pericytes undergo pathological phenotype switching, affecting their normal function in upholding structural stability and cross-communication with other cells. In the case of pancreatic ductal adenocarcinoma (PDAC), a significant portion of blood vessels are covered by an α-smooth muscle actin (αSMA)-expressing pericyte, which is normally absent from capillary pericytes. The DesminlowαSMAhigh phenotype was significantly correlated with intratumoral hypoxia and vascular leakiness. Using an in vitro co-culture system, we demonstrated that cancer cell-derived exosomes could induce ectopic αSMA expression in pericytes. Exosome-treated αSMA+ pericytes presented altered pericyte markers and an acquired immune-modulatory feature. αSMA+ pericytes were also linked to morphological and biomechanical changes in the pericyte. The PDAC exosome was sufficient to induce αSMA expression by normal pericytes of the healthy pancreas in vivo, and the vessels with αSMA+ pericytes were leaky. This study demonstrated that tumor pericyte heterogeneity could be dictated by cancer cells, and a subpopulation of these pericytes confers a pathological feature.

The unavailability of reliable models for studying breast cancer bone metastasis is the major challenge associated with poor prognosis in advanced-stage breast cancer patients. Breast cancer cells tend to preferentially disseminate to bone and colonize within the remodeling bone to cause bone metastasis. To improve the outcome of patients with breast cancer bone metastasis, we have previously developed a 3D in vitro breast cancer bone metastasis model using human mesenchymal stem cells (hMSCs) and primary breast cancer cell lines (MCF-7 and MDAMB231), recapitulating late-stage of breast cancer metastasis to bone. In the present study, we have tested our model using hMSCs and patient-derived breast cancer cell lines (NT013 and NT023) exhibiting different characteristics. We investigated the effect of breast cancer metastasis on bone growth using this 3D in vitro model and compared our results with previous studies. The results showed that NT013 and NT023 cells exhibiting hormone-positive and triple-negative characteristics underwent mesenchymal to epithelial transition (MET) and formed tumors in the presence of bone microenvironment, in line with our previous results with MCF-7 and MDAMB231 cell lines. In addition, the results showed upregulation of Wnt-related genes in hMSCs, cultured in the presence of excessive ET-1 cytokine released by NT013 cells, while downregulation of Wnt-related genes in the presence of excessive DKK-1, released by NT023 cells, leading to stimulation and abrogation of the osteogenic pathway, respectively, ultimately mimicking different types of bone lesions in breast cancer patients.

Tumor-derived extracellular vesicles (EVs) show great potential as biomarkers for several diseases, including pancreatic cancer, due to their roles in cancer development and progression. However, the challenge of utilizing EVs as biomarkers lies in their inherent heterogeneity in terms of size and concentration, making accurate quantification difficult, which is highly dependent on the isolation and quantification methods used. In our study, we compared three EV isolation techniques and two EV quantification methods. We observed variations in EV concentration, with approximately 1.5-fold differences depending on the quantification method used. Interestingly, all EV isolation techniques consistently yielded similar EV quantities, overall size distribution, and modal sizes. In contrast, we found a notable increase in total EV amounts in samples from pancreatic cancer cell lines, mouse models, and patient plasma, compared to non-cancerous conditions. Moreover, individual tumor-derived EVs exhibited at least a 3-fold increase in several EV biomarkers. Our data, obtained from EVs isolated using various techniques and quantified through different methods, as well as originating from various pancreatic cancer models, suggests that EV profiling holds promise for the identification of unique and cancer-specific biomarkers in pancreatic cancer.