Featured
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| Open AccessMolecular 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
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Article
| Open AccessBreast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling
Understanding the factors that hamper immune therapy in breast cancer may increase the range of patients who benefit. Here authors show that breast cancer cells produce and subsequently transfer active TGF-β type II receptors to CD8 + T cells to render them exhausted, thus paralyzing the anti-tumor immune response.
- Feng Xie
- , Xiaoxue Zhou
- & Fangfang Zhou
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Article
| Open AccessLysosomal protein transmembrane 5 promotes lung-specific metastasis by regulating BMPR1A lysosomal degradation
The mechanisms that confer lung-specific metastasis in renal cell carcinomas (RCC) remain to be detailed. Here the authors show that LAPTM5 contributes to lung-specific metastasis of RCCs by suppressing BMP signalling and thus, enhancing self-renewal and cancer stem cell-like traits of RCCs.
- Bo Jiang
- , Xiaozhi Zhao
- & Hongqian Guo
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Article
| Open AccessPRMT5 activates AKT via methylation to promote tumor metastasis
‘Protein arginine methyltransferase 5 (PRMT5) is known to regulate the expression of genes involved in metastasis. Here, the authors show that PRMT5 methylates Akt and methylation is required for phosphorylation and activation of Akt; ultimately leading to the increase in expression of pro-metastatic transcription factors.
- Lei Huang
- , Xiao-Ou Zhang
- & Qiong Wu
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Article
| Open AccessHigh throughput, label-free isolation of circulating tumor cell clusters in meshed microwells
Metastatic CTC clusters remain relatively unexplored due to the lack of optimized and practical technologies for their detection. Here the authors report Cluster-Wells to isolate CTC clusters in whole blood; they show this allows viable cluster retrieval for further molecular and functional analysis.
- Mert Boya
- , Tevhide Ozkaya-Ahmadov
- & A. Fatih Sarioglu
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Article
| Open AccessDeep neural network trained on gigapixel images improves lymph node metastasis detection in clinical settings
The pathological identification of lymph node metastasis in whole-slide images is demanding and tedious. Here, the authors design an artificial-intelligence-assisted assessment workflow to facilitate the routine counting of metastatic LNs.
- Shih-Chiang Huang
- , Chi-Chung Chen
- & Tse-Ching Chen
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Article
| Open AccessA lncRNA signature associated with tumor immune heterogeneity predicts distant metastasis in locoregionally advanced nasopharyngeal carcinoma
Long noncoding RNAs (lncRNAs) can be used for the development of prognostic signatures to predict tumour metastasis. Here the authors identify an immune-associated nine-lncRNA signature for predicting metastasis in a multicentre cohort of locoregionally advanced nasopharyngeal cancer patients.
- Ye-Lin Liang
- , Yuan Zhang
- & Na Liu
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Article
| Open AccessHomophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation
Direct contact between tumour cells and fibroblasts influences tumour cell behaviour. Here the authors show that pancreatic cancer cells and fibroblasts directly interact via homophilic ATP1A1 binding, which induces fibroblasts to secrete activin A to promote epithelial-mesenchymal transition of tumour cells and myofibroblast activation.
- Yi-Ing Chen
- , Chin-Chun Chang
- & Wen-Hwa Lee
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Article
| Open AccessPeptide nano-blanket impedes fibroblasts activation and subsequent formation of pre-metastatic niche
Primary tumors “spread the spark” by establishing a pre-metastatic niche. Here the authors develop an in-situ assembled peptide FR17 to serve as a “flame-retarding blanket” to extinguish the “fire” of the pre-metastatic microenvironment.
- Yi Zhou
- , Peng Ke
- & Jianqing Gao
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Article
| Open AccessTUBB4A interacts with MYH9 to protect the nucleus during cell migration and promotes prostate cancer via GSK3β/β-catenin signalling
The β-tubulin family protein TUBB4A is highly expressed in cancer but it’s molecular role is unclear. Here, the authors show that TUBB4A is required to protect the nucleus from genomic instability during migration and that it’s over expression promotes cancer progression.
- Song Gao
- , Shuaibin Wang
- & Lizhong Wang
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Article
| Open AccessEZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation
Breast cancer cells are known to metastasize to the bone but why the cells should migrate and metastasize to this particular organ is not clearly understood. Here, the authors show that EZH2 activates an integrin B1 and FAK signaling pathway in breast cancer cells, which activates TGFB signaling to drive metastasis in the bone.
- Lin Zhang
- , Jingkun Qu
- & Dihua Yu
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Article
| Open AccessHypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma
Ewing sarcoma tumour cells frequently metastasize to the bone but the molecular mechanisms governing this process are not well understood. Here, the authors show that neuropeptide Y/Y5 receptor pathway is activated in the hypoxic tumour microenvironment, which results in cytokinesis defects and chromosomal instability, leading to bone invasion.
- Congyi Lu
- , Akanksha Mahajan
- & Joanna Kitlinska
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Article
| Open AccessCooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis
The epithelial mesenchymal transition (EMT) is important in the metastatic spread of cancer cells. Here, the authors show that the EMT transcription factor, ZEB1, can modify estrogen receptor α during EMT and facilitate the migration of breast cancer cells to the bone
- Nastaran Mohammadi Ghahhari
- , Magdalena K. Sznurkowska
- & Didier Picard
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Article
| Open AccessIntegrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression
The molecular factors that drive invasiveness and metastasis in lung adenocarcinoma (LUAD) are not completely understood. Here, the authors use an integrative network approach to identify a gene signature of invasiveness in LUAD, and reveal Aurora kinases as master regulators of invasion.
- Seungyeul Yoo
- , Abhilasha Sinha
- & Charles A. Powell
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Article
| Open Accessp16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases
HER2+ breast cancer often develop brain metastases (BCBMs) that are difficult to treat. Here, the authors show that p16INK4A loss in BCBMs from HER2+ breast tumors results in resistance to the HER2 inhibitor Tucatinib, and that CDK4/6 inhibition can restore sensitivity to this drug.
- Jing Ni
- , Sheheryar Kabraji
- & Jean J. Zhao
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Article
| Open AccessCancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis
The contribution of breast cancer stem cells (BCSCs) to metastasis needs further elucidation. Here, the authors show that BCSCs secrete DKK1 to protect metastasizing cancer cells from ferroptosis via upregulation of SLC7A11, and further show that the combination of a ferroptosis inducer with a DKK1 inhibitor reduces metastasis.
- Mingming Wu
- , Xiao Zhang
- & Tao Zhu
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Article
| Open AccessFusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis
Fusobacterium nucleatum contributes to host epitranscriptomic modifications and colorectal cancer (CRC) development. Here, the authors show that Fusobacterium nucleatum reduces global m6A modifications to promote CRC metastasis through a YAP/FOXD3/METTL3/KIF26B axis.
- Shujie Chen,
- , Lu Zhang
- & Wei Zhuo
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Article
| Open AccessLin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression
The establishment of a pre-metastatic niche is a key step preceding metastasis formation. Here the authors show that tumor-intrinsic Lin28B, a RNA-binding protein, has an essential role in the formation of an immune-suppressive pre-metastatic niche, promoting lung metastasis of breast cancer.
- Meiyan Qi
- , Yun Xia
- & Lixing Zhan
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Article
| Open AccessA non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis
Hexokinase 2 expression is markedly induced in cancer cells and contributes to cancer cell metabolism. Here, the authors show that hexokinase 2 can contribute to the metastatic spread of cancer cells independently of its glycolytic function via inhibiting the activity of GSK3β, which in turn elevates the protein levels of the EMT transcription factor SNAIL.
- Catherine S. Blaha
- , Gopalakrishnan Ramakrishnan
- & Nissim Hay
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Article
| Open AccessReceptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis
Distant metastasis is a major reason for mortality in patients with prostate cancer (PC). Here, the authors show that receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and its targeting impairs PC metastasis development.
- Yiwu Yan
- , Bo Zhou
- & Wei Yang
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Article
| Open AccessMapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities
The molecular landscape of breast cancer brain metastases (BCBM) is still understudied, especially for different breast cancer subtypes. Here, the authors characterise subtype-specific BCBMs using genomics and transcriptomics and identify homologous recombination deficiency as a key therapeutic vulnerability.
- Nicola Cosgrove
- , Damir Varešlija
- & Leonie S. Young
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Article
| Open AccessGenomic alterations and evolution of cell clusters in metastatic invasive micropapillary carcinoma of the breast
Invasive micropapillary carcinoma (IMPC) is a highly metastatic rare form of breast cancer but its genomic alterations are largely unknown. Here, the authors show that monoclonal metastatic ancestors share copy-number loss of PRDM16 and IGSF9 and gain of ALDH2 in primary samples from IMPC patients.
- Qianqian Shi
- , Kang Shao
- & Li Fu
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Article
| Open AccessNicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer
The mechanism of how VEGF-C is regulated to promote lymphatic metastasis of oesophageal cancer is unclear. Here the authors show that nicotine prevents the mRNA decay of VEGF-C mRNA and promotes lymphatic metastasis by downregulating deubiquitinase OTUD3 and RNA binding protein ZFP36.
- Meng Wang
- , Yue Li
- & Libing Song
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Article
| Open AccessDeep learning for the prediction of early on-treatment response in metastatic colorectal cancer from serial medical imaging
Evaluation of tumor response to antivascular endothelial growth factor therapies in metastatic colorectal cancer (mCRC) is limited because morphological change in tumor may occur earlier or be more critical than tumor size change. Here, the authors present an analysis utilizing a deep learning network to characterize tumor morphological change as well as tumor size changes for response assessment in mCRC patients.
- Lin Lu
- , Laurent Dercle
- & Lawrence H. Schwartz
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Article
| Open AccessIndependent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine
Small intestine neuroendocrine tumors (SI-NETs) are frequently multifocal and metastatic, but their tumourigenesis is still poorly understood. Here, the authors analyse multifocal SI-NET tumours with whole-genome sequencing, revealing the landscape of genomic alterations and frequent polyclonal origins.
- Erik Elias
- , Arman Ardalan
- & Erik Larsson
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Article
| Open AccessThe EMT activator ZEB1 accelerates endosomal trafficking to establish a polarity axis in lung adenocarcinoma cells
The way in which metastatic tumour cells control endocytic vesicular trafficking networks to establish a front-rear polarity axis that facilitates motility remains unclear. Here, the authors show that the EMT activator ZEB1 influences vesicular trafficking dynamics to execute cell polarity change.
- Priyam Banerjee
- , Guan-Yu Xiao
- & Jonathan M. Kurie
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Article
| Open AccessSomatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
Biomarkers of prostate cancer metastasis have been difficult to determine with confidence. Here the authors analyse mutation prevalence in 1844 prostate cancers and show that ZNRF3 loss is enriched in metastatic, castration-resistant prostate cancer and associated with metastasis of localized disease.
- Michael Fraser
- , Julie Livingstone
- & Paul C. Boutros
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Article
| Open AccessLung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3
The formation of the pre-metastatic niche enables the colonisation of disseminated cancer cells in distant organs. Here, the authors show that Th2 cytokines induce Complement 3 production in lung mesenchymal stromal cells, which recruits neutrophils and promotes the formation neutrophil extracellular traps, facilitating breast cancer cell metastasis to the lungs.
- Zhiyuan Zheng
- , Ya-nan Li
- & Yufang Shi
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Article
| Open AccessPhase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis
Leptomeningeal metastases from solid tumors are a rare complication with a very poor prognosis. Here the authors report the efficacy and safety of combined ipilimumab and nivolumab in patients with leptomeningeal carcinomatosis.
- Priscilla K. Brastianos
- , Matthew R. Strickland
- & Ryan J. Sullivan
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Article
| Open AccessGenomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases
Leptomeningeal disease (LMD) is a serious complication of metastatic solid tumors with a poor prognosis. Here, by using single-cell RNA sequencing of cerebrospinal fluid, the authors report genomic and immune correlates of response to immunotherapy in two cohorts of patients with LMD treated with immune checkpoint inhibitors.
- Sanjay M. Prakadan
- , Christopher A. Alvarez-Breckenridge
- & Alex K. Shalek
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Article
| Open AccessHomeostatic membrane tension constrains cancer cell dissemination by counteracting BAR protein assembly
Changes in cell mechanics contribute to cancer cell dissemination. Here the authors show that high plasma membrane (PM) tension inhibits cancer dissemination by counteracting mechanosensitive BAR family protein assembly, while restoration of PM tension phenotypically convert malignant cells into a non-motile epithelial cell state.
- Kazuya Tsujita
- , Reiko Satow
- & Toshiki Itoh
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Article
| Open AccessDeterminants of renal cell carcinoma invasion and metastatic competence
Tumour thrombi (TT) are intravascular extensions of renal cell carcinomas (RCC) which often lead to distant metastases. Here the authors examine the determinants of vascular invasion and metastasis in a unique cohort of RCC patients with TT using multi-region genomics and in vivo models.
- Kangsan Kim
- , Qinbo Zhou
- & Srinivas Malladi
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Article
| Open AccessLoss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression
The molecular underpinnings driving uveal melanoma (UM) progression are unknown. Here the authors show that loss of Polycomb Repressive Complex 1 triggers chromosomal instability, which promotes inflammatory signaling and migration in UM.
- Mathieu F. Bakhoum
- , Jasmine H. Francis
- & Ashley M. Laughney
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Article
| Open AccessLong non-coding RNA NR2F1-AS1 induces breast cancer lung metastatic dormancy by regulating NR2F1 and ΔNp63
Disseminated tumor cells often become dormant before awakening for metastatic growth. Here, the authors report that the lncRNA, NR2F1-AS1, is upregulated in dormant mesenchymal-like breast cancer stem-like cells and promotes dissemination but inhibits proliferation, leading to metastatic dormancy.
- Yingjie Liu
- , Peiyuan Zhang
- & Guohong Hu
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Article
| Open AccessDysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer
High cholesterol has been associated with increased risk of cancer but the underlying mechanism is not completely understood. Here, the authors show that a cholesterol metabolite induces metabolic reprogramming that generates ferroptosis-resistant cancer cells leading to increased tumour growth and metastasis.
- Wen Liu
- , Binita Chakraborty
- & Donald P. McDonnell
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Article
| Open AccessEpigenetic control of melanoma cell invasiveness by the stem cell factor SALL4
Melanoma cells can switch between proliferative and invasive phenotypes. Here the authors show that the embryonic stem cell factor Sall4 is a negative regulator of melanoma phenotype switching where its loss leads to the acquisition of an invasive phenotype, due to derepression of invasiveness genes.
- Johanna Diener
- , Arianna Baggiolini
- & Lukas Sommer
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Article
| Open AccessICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer
Circulating tumor cell (CTC) clusters are more efficient at mediating metastasis as compared to single cells and are associated with poor prognosis in breast cancer. Here, the authors show that ICAM1 is enriched in CTC clusters and its loss suppresses cell-cell interaction and CTC cluster formation, and propose ICAM1 as a therapeutic target for treating breast cancer metastasis.
- Rokana Taftaf
- , Xia Liu
- & Huiping Liu
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Article
| Open AccessThe HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling
Hypoxia plays a critical role in tumor progression including invasion and metastasis. Here, the authors screened several hypoxia inducible genes and identified the oncogenic role of MAFF in breast cancer metastasis and that it activates IL11/STAT3 pathway.
- Eui Jung Moon
- , Stephano S. Mello
- & Amato J. Giaccia
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Article
| Open AccessEngineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer
Bone metastases are associated with poor prognosis in patients with breast cancer and limited therapeutic options. Here the authors exploit near-infrared light responsive macrophages for the tumor-selective delivery of oxaliplatin prodrug for chemo-photodynamic therapy of primary and bone metastatic breast cancer.
- Yanjuan Huang
- , Zilin Guan
- & Chunshun Zhao
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Article
| Open AccessDissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma
Circulating tumour cells can be useful for monitoring disease progression but how they survive in the circulatory system is unclear. Here, the authors use single-cell sequencing of circulating tumour cells from multiple vascular sites in liver cancer patients and identify genes that may help the cells survive.
- Yun-Fan Sun
- , Liang Wu
- & Xin-Rong Yang
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Article
| Open AccessImpairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis
Endo180, a collagen binding receptor, is highly expressed in a subset of cancer-associated fibroblasts. The authors show, using knockout mice and 3D in vitro assays, that Endo180 depletion impairs tumour fibroblast contractility and viability resulting in reduced tumour growth and metastasis.
- Ute Jungwirth
- , Antoinette van Weverwijk
- & Clare M. Isacke
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Article
| Open AccessTumor microenvironmental cytokines bound to cancer exosomes determine uptake by cytokine receptor-expressing cells and biodistribution
Cancer derived exosomes are reported to promote metastatic dissemination. Here the authors show that cytokines in the tumor microenvironment bind to exosomes via glycosaminoglycan side chains of proteoglycans, and these exosomes are preferentially taken up by specific cell lineages and organs to promote metastasis.
- Luize G. Lima
- , Sunyoung Ham
- & Andreas Möller
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Article
| Open AccessSystemic metastasis-targeted nanotherapeutic reinforces tumor surgical resection and chemotherapy
Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Here, the authors show that a systemic metastasis-targeted nanotherapeutic may offer a powerful adjunct therapy for suppressing tumor metastasis.
- Minjun Xu
- , Kaili Hu
- & Jun Chen
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Article
| Open AccessCell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer
It is currently unclear if cell-free DNA samples from metastatic cancers are as informative as tissue ones for cancer profiling. Here the authors show that cell-free DNA samples from rapid autopsies capture clonal and subclonal alterations of metastatic tumours and reveal more driver alterations than single tissue samples.
- Bernard Pereira
- , Christopher T. Chen
- & Dejan Juric
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Article
| Open AccessAn RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness
Activated Notch signalling promotes cancer metastasis and stemness. Here the authors show that Notch1 activates transcription of DNA replication factor RCF4 and that RCF4 binds and stabilises Notch1 intracellular domain (NICD1) to promote cancer metastasis.
- Lei Liu
- , Tianyu Tao
- & Han Tian
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Article
| Open AccessIFN-γ-dependent NK cell activation is essential to metastasis suppression by engineered Salmonella
Cancer metastasis is one of the major causes of cancer related deaths and there is an urgent need to find more clinically effective metastasis targeting agents. Here, the authors show that Salmonella YB1 inhibits metastasis in multiple mouse models of cancer through a mechanism dependent on IFN-γ and NK cells.
- Qiubin Lin
- , Li Rong
- & Jian-Dong Huang
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Article
| Open AccessCancer of unknown primary stem-like cells model multi-organ metastasis and unveil liability to MEK inhibition
Cancer of unknown primary (CUP) is a mysterious malignancy featuring metastatic dissemination in the absence of a recognizable primary tumor. By characterizing CUP cancer stem cells we show that self-sustained long-term propagation and sensitivity to MEK inhibition are CUP common features.
- Federica Verginelli
- , Alberto Pisacane
- & Carla Boccaccio
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Article
| Open AccessCo-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy
Some chemotherapeutic drugs, such as doxorubicin, induce immunogenic cell death (ICD) and promote anti-tumor immune responses. Here the authors report that the histone demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX1) reduces the expression of PD-L1 in cancer cells and enhances doxorubicin-induced ICD, promoting T cell infiltration and reducing tumor growth in preclinical models.
- Jing Liu
- , Zhihao Zhao
- & Youqing Shen
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Article
| Open AccessSuppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells
Pancreatic ductal adenocarcinoma has a collagen-rich dense extracellular matrix that promotes malignancy of cancer cells. Here, the authors show that fibrillar collagen that is cancer-cell-derived, but not stroma-derived, selectively restrains tumor growth under control of their pC-proteinase, BMP1.
- Chenxi Tian
- , Ying Huang
- & Richard O. Hynes