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Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
Metastasis arises from disseminated tumour cells (DTCs) while the underlying mechanism of DTCs plasticity remains underexplored. Here, the authors show that spatially organized oncogenic enhancers on chromatin sustain the establishment of retinoic acid (RA)-stimulated transcriptional memory through activation of SOX9, supporting the escape of quiescent DTCs from NK-mediated immune surveillance.
- Daniela Michelatti
- , Sven Beyes
- & Alessio Zippo
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Article
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The evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis
Detailed molecular studies are required to understand the differences between primary and metastatic upper tract urothelial carcinoma (UTUC). Here, the authors use genomics, transcriptomics and imaging mass cytometry to characterise the molecular profiles of primary and metastatic UTUC, and find that molecular subtypes remain highly conserved.
- Kentaro Ohara
- , André Figueiredo Rendeiro
- & Juan Miguel Mosquera
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Long noncoding RNA Malat1 protects against osteoporosis and bone metastasis
MALAT1 is a long non-coding RNA that is known to suppress breast cancer lung metastasis. Here the authors show that MALAT1 is downregulated during osteoclastogenesis and its loss derepresses Tead3, promoting Nfatc1-mediated osteoclast differentiation and enhancing bone metastasis.
- Yang Zhao
- , Jingyuan Ning
- & Li Ma
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Article
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Causes of death among people living with metastatic cancer
Studying survivorship and causes of death in patients with metastatic cancer remains an important task. Here, the authors characterise the causes of death in over a million patients with metastatic cancer, and predict the risk of death after diagnosis due to cancer-related or other causes.
- Kyle Mani
- , Daxuan Deng
- & Nicholas G. Zaorsky
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Oncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis
The molecular mechanisms of lung cancer metastasis remain incompletely understood. Here the authors show that the transcription factor ZBTB11 drives metastasis in preclinical models of lung cancer both through SE translocation (SET)-dependent and independent manner.
- Wenbin Xu
- , Han Yao
- & Donglai Wang
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Article
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Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation
The molecular mechanisms underlying Double-Null Prostate Cancer (DNPC) pathogenesis remain elusive. Here, the authors show that co-activation of HGF/MET and Wnt/β-catenin signaling in mouse prostates results in DNPC-like tumor lesions with elevated expression of XPO1 and ribosomal proteins.
- Won Kyung Kim
- , Alyssa J. Buckley
- & Zijie Sun
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Article
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Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation
Mechanisms underlying sex associated differences in the role of androgen receptor (AR) in melanoma are unclear. Here the authors show that androgen-activated AR transcriptionally upregulates fucosyltransferase 4, which fucosylates L1CAM and promotes melanoma invasiveness by disrupting adherens junctions.
- Qian Liu
- , Emma Adhikari
- & Eric K. Lau
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Aneuploid embryonic stem cells drive teratoma metastasis
Aneuploidy is associated with cancer metastasis, but the causal relationship between them is unclear. Here the authors show that aneuploid murine embryonic stem cells lead to teratomas that can spread to multiple organs without requiring additional driver gene mutations and identify unique cell populations with high stemness in aneuploid teratomas.
- Rong Xiao
- , Deshu Xu
- & Yue Huang
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Article
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HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis
The drivers of melanoma brain metastases (MBM) remain poorly understood. Here, the authors identify stress-induced HDAC8 activity as the driver of a neural crest-stem cell like transcriptional state that leads to MBM, and explore the molecular mechanism that drives this transition.
- Michael F. Emmons
- , Richard L. Bennett
- & Keiran S. M. Smalley
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Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype
Breast cancer leptomeningeal metastasis is difficult to assess due to the site. Here, the authors assess cerebrospinal fluid cell-free DNA to show specific mutations present in leptomeningeal metastasis, and develop organoids of the disease.
- Amanda Fitzpatrick
- , Marjan Iravani
- & Clare M. Isacke
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Article
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Temporal chromatin accessibility changes define transcriptional states essential for osteosarcoma metastasis
The genomic and epigenomic landscape during metastasis in osteosarcoma remains to be investigated. Here, functional and pharmacological studies identify the dynamic epigenomic changes and gene vulnerabilities during the formation of osteosarcoma tumours in the lung microenvironment.
- W. Dean Pontius
- , Ellen S. Hong
- & Peter C. Scacheri
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Article
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Metabolic dependencies of metastasis-initiating cells in female breast cancer
Understanding the mechanisms associated with cancer metastasis may help control cancer progression. Here the authors investigate the metabolism of metastasis initiating cells in breast cancer and show that their metastatic ability relies on fatty acid oxidation and the oxidative tricarboxylic acid cycle, which in turn regulates acetyl-CoA generation and the acetylation of histones on EMT related genes.
- C. Megan Young
- , Laurent Beziaud
- & Joerg Huelsken
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A circular RNA activated by TGFβ promotes tumor metastasis through enhancing IGF2BP3-mediated PDPN mRNA stability
TGFbeta is known to promote cancer metastasis through the promotion of epithelial-mesenchymal transition (EMT). Here, the authors demonstrate that a TGFbeta induced circular RNA (circITGB6) promotes colorectal cancer metastasis via activation of the m6A reader protein, IGF2BP3, resulting in stabilization of an EMT-promoting gene, PDPN.
- Ke Li
- , Jiawei Guo
- & Yong Peng
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The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer
The suppressive immune microenvironment in colorectal cancer (CRC) liver metastasis remains to be explored. Here, the authors find tumor-associated macrophages in the liver microenvironment induces elevated secretion of FGL1 from cancer cells and hepatocytes which promotes CRC metastasis by suppressing the infiltration of T cells.
- Jia-Jun Li
- , Jin-Hong Wang
- & Huai-Qiang Ju
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Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice
The liver is the most common site of metastasis for pancreatic ductal adenocarcinoma (PDAC). Here, the authors demonstrate that β-glucan, a microbial component associated with trained immunity, activates liver-resident macrophages (Kupffer cells) and prevents PDAC metastasis to the liver
- Stacy K. Thomas
- , Max M. Wattenberg
- & Gregory L. Beatty
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Article
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YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis
Small cell lung cancers (SCLC) have often inactivating mutations in RB1. In this study, the authors demonstrate that RB1 loss mediates low expression of YAP1 in SCLC tumors ultimately promoting metastasis and they propose to use benzamide family HDAC inhibitors to induce YAP1 expression for prevention of metastases.
- Zhengming Wu
- , Junhui Su
- & Kun-Liang Guan
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Theranostic imaging and multimodal photodynamic therapy and immunotherapy using the mTOR signaling pathway
Approaches to combine photodynamic therapy (PDT) with immunotherapy are emerging, allowing the treatment of primary and metastatic tumors. Here the authors report the design and characterization of a nanomaterial for theranostic imaging and photodynamic therapy eliciting anti-tumor immune response in preclinical cancer models.
- Huiling Zhou
- , Dongsheng Tang
- & Haihua Xiao
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Citrullinated fibrinogen-SAAs complex causes vascular metastagenesis
The identification of factors that contribute to pre-metastatic niche can help prevent initial metastasis. Here the authors show that citrullinated fibrinogen complexes with serum amyloid A proteins (SAAs) to form a pre-metastatic niche in patients.
- Yibing Han
- , Takeshi Tomita
- & Sachie Hiratsuka
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Article
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Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis
The metastatic tumour microenvironment in pancreatic ductal adenocarcinoma (PDAC) remains to be explored. Here, the authors perform single cell RNA sequencing analysis for synchronously resected PDAC primary tumours and matched liver metastases and find differences in cellular composition.
- Shu Zhang
- , Wen Fang
- & Ying Lv
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An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver
Cancer liver metastases can be encapsulated by a fibrotic stroma. Here the authors use digital pathology to generate spatial growth pattern maps of colorectal cancer liver metastasis and show that prognosis depends on the degree of fibrotic encapsulation.
- Carlos Fernández Moro
- , Natalie Geyer
- & Marco Gerling
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Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis
The genomic landscape of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) remains to be explored. Here, the authors analyse a cohort of 233 patients with BM including 47 primary tumour, 42 extracranial metastatic matched samples and reveal distinct mutational patterns.
- Anna Skakodub
- , Henry Walch
- & Luke R. G. Pike
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A synthetic metastatic niche reveals antitumor neutrophils drive breast cancer metastatic dormancy in the lungs
3D scaffolds can be used to recapitulate key aspects of the microenvironment of primary tumors and metastatic organs. Here the authors use subcutaneous porous 3D scaffold implants as a tool to study the immune signals in the lungs of metastatic breast cancer, revealing multifaceted roles of neutrophils in regulating lung metastasis.
- Jing Wang
- , Ramon Ocadiz-Ruiz
- & Lonnie D. Shea
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SIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma
The tumour-specific functions of SIX1 homeoprotein in Ewing sarcoma (ES) remain poorly understood. Here, the authors suggest that SIX1, which enhances metastasis in most tumour types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes.
- Connor J. Hughes
- , Kaiah M. Fields
- & Heide L. Ford
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Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer
Distinguishing the drivers of metastasis versus those of the primary tumour in breast cancer remains challenging. Here, the authors explore primary-only, metastatic-only, and shared drivers in breast cancer using mammary-specific transposon mutagenesis screens, which leads to potential therapeutic targets to prevent metastasis.
- Zhe Jiang
- , YoungJun Ju
- & Eldad Zacksenhaus
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Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer
HER2 amplification in metastatic colorectal cancer (mCRC) identifies a group of patients with poorer prognosis. Here, the authors report the results of a phase II clinical trial assessing the clinical response and safety of trastuzumab deruxtecan as a third-line treatment in patients with mCRC with different HER2 expression levels
- Takayuki Yoshino
- , Maria Di Bartolomeo
- & Maria Di Bartolomeo
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Identification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer
Long-term metastatic relapse is observed in patients with luminal breast cancer (BC). Here, the authors show that fatty acid amide hydrolase is a tumour suppressor for lung metastasis in mouse models of BC and a predictor of metastasis in patients with luminal BC.
- Isabel Tundidor
- , Marta Seijo-Vila
- & Eduardo Pérez-Gómez
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Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment
Astrocytes can influence several steps of the metastatic process in the brain. Here the authors show that type I interferon response in astrocytes facilitates brain metastasis by increasing recruitment of tumor promoting monocytic myeloid cells.
- Weili Ma
- , Maria Cecília Oliveira-Nunes
- & Qing Chen
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Article
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HAPLN1 potentiates peritoneal metastasis in pancreatic cancer
The presence of peritoneal metastasis in pancreatic cancers is associated with poor prognosis. Here the authors show that hyaluronan and proteoglycan link protein-1 (HAPLN1) promotes tumour cell plasticity and pro-tumoral immune microenvironment to facilitate peritoneal dissemination in pancreatic cancers.
- Lena Wiedmann
- , Francesca De Angelis Rigotti
- & Juan Rodriguez-Vita
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Single cell analysis in head and neck cancer reveals potential immune evasion mechanisms during early metastasis
The molecular mechanisms underlying lymph-node metastasis in head and neck squamous-cell carcinoma remain to be investigated. Here, the authors perform single-cell RNA sequencing of cancer cells and CD8 + T cells and suggest potential mechanisms of immune evasion during early metastasis.
- Hong Sheng Quah
- , Elaine Yiqun Cao
- & N. Gopalakrishna Iyer
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Article
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Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) cells can utilise the tumour microenvironment to metastasise to the liver. Here the authors show that hepatoctyes overexpress SLIT2 to enable premetastatic niche formation for ROBO1-positive PDAC cells to support the survival of these tumour cells in the liver.
- Qing Li
- , Xiao-Xin Zhang
- & Zhi-Gang Zhang
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Article
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Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer
Implementing high-throughput single-cell DNA sequencing for the study of solid tumours has been challenging. Here, the authors present an optimised approach for snap-frozen tissue single nuclei extraction and DNA sequencing, which can be applied to study pancreatic ductal adenocarcinoma evolution and heterogeneity.
- Haochen Zhang
- , Elias-Ramzey Karnoub
- & Christine A. Iacobuzio-Donahue
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Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance
It is critical to understand the factors that are associated with nasopharyngeal carcinoma (NPC) progression, metastasis and response to therapy. Here, the authors analyse primary and metastatic NPC samples using bulk and single-cell sequencing, and find two distinct evolutionary routes that lead to metastasis.
- Mei Lin
- , Xiao-Long Zhang
- & Ming-Yuan Chen
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Mapping lesion-specific response and progression dynamics and inter-organ variability in metastatic colorectal cancer
Understanding the heterogeneity of growth, response to therapy and progression dynamics in metastatic colorectal cancer (mCRC) remains critical. Here, the authors analyse lesion-specific response heterogeneity in 4,308 mCRC patients and find that organ-level progression sequence is associated with long-term survival.
- Jiawei Zhou
- , Amber Cipriani
- & Yanguang Cao
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Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer
While EGFR-targeted therapies have clinical benefit, drug-resistant brain metastases present a major obstacle. Here, the authors identify a genetic signature in brain metastatic lesions associated with osimertinib resistance and find RhoA to have an important role in the resulting phenotype.
- Sally J. Adua
- , Anna Arnal-Estapé
- & Don X. Nguyen
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EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis
Enhancer of zeste homolog 2 (EZH2) has been associated with poor prognosis in triple negative breast cancer (TNBC). Here, the authors suggest a potential role for trimethylation function of EZH2 in driving peritoneal metastasis in TNBC.
- Ayushi Verma
- , Akhilesh Singh
- & Dipak Datta
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Article
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Decoding molecular programs in melanoma brain metastases
Melanoma brain metastases (MBM) show heterogeneous therapeutic response determined by incompletely understood mechanisms. Here, the authors use a multi-OMICS approach and targeted sequencing (TargetSeq) to decipher programs that may define molecular subsets of MBM and their response to therapy.
- Josefine Radke
- , Elisa Schumann
- & Torben Redmer
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Article
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Connecting multiple microenvironment proteomes uncovers the biology in head and neck cancer
The biological understanding of poor prognosis associated with lymph node metastasis in head and neck cancer (HNC) remains crucial. Here, a proteomic characterisation of 140 multisite samples from a 59-HNC patient cohort and machine learning reveals potential biomarkers and metastasis related signatures.
- Ariane F. Busso-Lopes
- , Leandro X. Neves
- & Adriana F. Paes Leme
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Article
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Collaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer
The Bladder Cancer Advocacy Network established the UC-GENOME study in order to create a biobank and data repository for metastatic urothelial carcinoma. Here, the authors present the first characterization and analysis of DNA and RNA sequencing data from the 218 patients included in the UC-GENOME.
- Jeffrey S. Damrauer
- , Wolfgang Beckabir
- & Matthew I. Milowsky
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Article
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Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation
Cytoplasmic accumulation of RNA binding protein, hnRNPK in cancer cells is associated with poor prognosis. Here the authors show that SCFFbxo4 E3 ubiquitin ligase-mediated polyubiquitylation of hnRNPK restricts c-Myc translation and limits cancer progression.
- Bartosz Mucha
- , Shuo Qie
- & J. Alan Diehl
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Article
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FOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis
Forkhead box transcription factor, FOXQ1 is reported to promote epithelial-mesenchymal transition (EMT) and cancer metastasis. Here the authors show that FOXQ1 recruits the KMT2/MLL histone methyltransferase complex as a transcriptional coactivator to activate EMT programme in breast cancer.
- Allison V. Mitchell
- , Ling Wu
- & Guojun Wu
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Article
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ESRP1-regulated isoform switching of LRRFIP2 determines metastasis of gastric cancer
ESRP1 is reported to regulate the alternative splicing of some genes involved in epithelial–mesenchymal transition. Here the authors show that LRRFIP2 is a target of ESRP1 and that two spliced variants of LRRFIP2 have opposing functions in gastric cancer metastasis
- Jihee Lee
- , Kyoungwha Pang
- & Seong-Jin Kim
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Article
| Open Access
Divergent regulation of basement membrane trafficking by human macrophages and cancer cells
Cancer cells and macrophages can infiltrate and remodel the extracellular matrix (ECM). Here, by using native basement membrane-interstitial matrix explants as model and live cell confocal imaging, the authors reveal divergent mechanisms used by cancer cells and macrophages to penetrate native basement membrane barriers.
- Julian C. Bahr
- , Xiao-Yan Li
- & Stephen J. Weiss
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Article
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Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression
Methylmalonic acid (MMA) is increased in aging as well as produced by advanced tumors, and can drive pro-aggressive changes in these tumor cells. Here, the authors show that MMA can also act on fibroblasts in the tumor microenvironment, recruiting and activating them to further support tumor progression.
- Zhongchi Li
- , Vivien Low
- & John Blenis
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Article
| Open Access
Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis
Cell migration regulates diverse (patho)physiological processes, including cancer metastasis. Here the authors show that the chloride ion channel SWELL1 and the ion exchanger NHE1 are preferentially enriched at the trailing and leading edges, respectively, of migrating cells and regulate cell volume to propel confined cells, favouring breast cancer cell extravasation and metastasis.
- Yuqi Zhang
- , Yizeng Li
- & Konstantinos Konstantopoulos
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Article
| Open Access
The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis
Brain metastases (BrMs) in non-small cell lung cancer (NSCLC) are associated with dismal outcomes, and are possibly sustained by the brain microenvironment. Here, the authors analyse NSCLC BrMs using Digital Spatial Profiling and reveal fibrosis, immune suppression, and cell reprogramming in the BrM microenvironment.
- Qi Zhang
- , Rober Abdo
- & Shawn Shun-Cheng Li
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Article
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Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer
Accumulating evidence suggest that chemotherapy could paradoxically promote cancer metastasis. Here the authors report that, in preclinical breast cancer models, adjuvant treatment with doxorubicin induces the formation of an immunosuppressive metastatic niche that promotes relapse but that can be reverted with pharmacological blockade of complement signaling.
- Lea Monteran
- , Nour Ershaid
- & Neta Erez
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Article
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A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma
Metastatic clear cell renal cell carcinoma has a poor prognosis. Here, the authors use single cell RNA-seq to show a distinct gene expression signature in the primary tumour of metastatic patients, and highlights immune cell receptor interactions as potential therapeutic targets.
- Adele M. Alchahin
- , Shenglin Mei
- & Ninib Baryawno
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Article
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The SWI/SNF chromatin remodeling factor DPF3 regulates metastasis of ccRCC by modulating TGF-β signaling
The functional role of DPF3, a component of the SWI/SNF chromatin remodelling complex associated with clear cell renal cell carcinoma (ccRCC), remains unknown. Here, the authors characterise the mechanism by which DPF3 promotes metastasis via the activation of the TGF-β signalling pathway in ccRCC.
- Huanhuan Cui
- , Hongyang Yi
- & Wei Chen
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Article
| Open Access
Molecular characterization of colorectal cancer related peritoneal metastatic disease
Colorectal cancer can lead to the development of peritoneal metastases, which are associated with worse disease outcome. Here, the authors characterize peritoneal metastases from 52 patients using RNA-seq and mutational sequencing and show a distinct molecular subtype.
- Kristiaan J. Lenos
- , Sander Bach
- & Louis Vermeulen
Cell surface patching via CXCR4-targeted nanothreads for cancer metastasis inhibition