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| Open AccessIn vivo microscopy reveals macrophage polarization locally promotes coherent microtubule dynamics in migrating cancer cells
The regulation of microtubule (MT) dynamics in cancer cells within the tumor microenvironment is less understood. Here, the authors develop an imaging platform to examine MT dynamics in live xenograft models and show that pro-tumor macrophages modulate MT coherence and alignment to promote cancer cell migration.
- Gaurav Luthria
- , Ran Li
- & Miles A. Miller
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Article
| Open AccessChronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice
Circadian disruption is implicated in the development of different human cancers. Here the authors show that chronic circadian disruption, through continuous jet lag, only moderately affects primary tumour growth but promotes cancer-cell dissemination and metastasis in a mouse model of spontaneous mammary tumorigenesis.
- Eva Hadadi
- , William Taylor
- & Hervé Acloque
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Article
| Open AccessDual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma
The tumour microenvironment plays an important role in promoting glioblastoma. Here, the authors show that glioma stem cells secrete WISP1, which promotes both the survival of the stem cells and tumour-associated macrophages.
- Weiwei Tao
- , Chengwei Chu
- & Shideng Bao
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Article
| Open AccessRab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth
Mechanisms governing adaptation of breast cancer to the brain metastatic microenvironment are unclear. Here, the authors use RNA-sequencing and Drosophila screening to identify Rab11b-mediated endosomal recycling as a unique mechanism for adaptation to a challenging metastatic microenvironment, which can be exploited by repurposing statins.
- Erin N. Howe
- , Miranda D. Burnette
- & Siyuan Zhang
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Article
| Open AccessMYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies
Oncogene addiction is considered as a cancer cell-autonomous phenomenon, but can also influence the host immune system. Here the authors show that MYC-driven lymphomagenesis is associated with a block in the maturation and effector functions of natural killer cells as a mechanism of tumor escape from immunosurveillance.
- Srividya Swaminathan
- , Aida S. Hansen
- & Dean W. Felsher
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Article
| Open AccessPericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth
Focal adhesion kinase (FAK) is required for tumour angiogenesis and growth. Here, the authors show that deletion of pericyte FAK upregulates Gas6-Axl mediated Cyr61 production, which increases endothelial cell proliferation and angiogenesis, while elevating tissue factor production to enhance tumour cell proliferation.
- Tanguy Lechertier
- , Louise E. Reynolds
- & Kairbaan M. Hodivala-Dilke
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Article
| Open AccessSingle-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma
Understanding the mechanisms that lead to lung adenocarcinoma metastasis is important for identifying new therapeutics. Here, the authors document the changes in the transcriptome of human lung adenocarcinoma using single-cell sequencing and link cancer cell signatures to immune cell dynamics.
- Nayoung Kim
- , Hong Kwan Kim
- & Hae-Ock Lee
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Article
| Open AccessEffective combinatorial immunotherapy for penile squamous cell carcinoma
Penile squamous cell carcinoma (PSCC) is a cancer that is associated with significant mortality. Here, the authors develop a mouse model of PSCC by co-deletion of Smad4 and Apc in the androgen-responsive penile epithelium, and show synergistic efficacy of checkpoint therapy with cabozantinib or celecoxib in their model.
- Tianhe Huang
- , Xi Cheng
- & Xin Lu
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Article
| Open AccessEndothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance
The cell adhesion molecule E-selectin regulates haematopoietic stem cell self-renewal in the bone marrow vascular niche. Here, the authors show E-selectin adhesion directly induces survival signaling in acute myeloid leukaemia and therapeutic inhibition improves chemotherapy outcomes in mice.
- Valerie Barbier
- , Johanna Erbani
- & Ingrid G. Winkler
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Article
| Open AccessSpatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma
Immunotherapies now dominate the treatment landscape for melanoma, but why they only work in a subset of patients remains unclear. Here, the authors perform an immunogenomic analysis on 67 intratumor sub-regions of a PD-1 inhibitor resistant melanoma, and 2 additional metastases from a single patient, mapping the spatial relationships between genomic and immune heterogeneity at high resolution.
- Akash Mitra
- , Miles C. Andrews
- & P. Andrew Futreal
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Article
| Open AccessPotent BRD4 inhibitor suppresses cancer cell-macrophage interaction
Inhibitors of the BET family proteins are limited by their potency and oral bio-availability. Here, the authors report a new BET inhibitor, NHWD-870, with improved potency compared to previous BET inhibitors, and show that it suppresses BRD4 and targets tumour associated macrophages.
- Mingzhu Yin
- , Ying Guo
- & Qin Yan
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Article
| Open AccessTGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking
TGFβ has a role in cancer immunosuppression but the exact mechanisms haven’t been fully elucidated. Here, using mouse models deficient in TGFβ-signaling, the authors show that loss of ALK5 in CD8 + T cells enhances their tumour trafficking and cytotoxicity suggesting that ALK5 inhibitors may have clinical utility.
- Andrew J. Gunderson
- , Tomoko Yamazaki
- & Kristina H. Young
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Article
| Open AccessAn open source and reduce expenditure ROS generation strategy for chemodynamic/photodynamic synergistic therapy
The supply of oxygen species for dynamic therapy is a major limitation. Here, the authors report on a complex of calcium peroxide with photo/chemo dynamic agents, where NIR heating causes the release of calcium peroxide to generate oxygen and hydrogen peroxide for photodynamic and chemodynamic therapy.
- Conghui Liu
- , Yu Cao
- & Haifeng Dong
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Article
| Open AccessDifferential regulation of breast cancer bone metastasis by PARP1 and PARP2
The effect of PARP inhibitors on bone mass and bone metastasis are unclear. Here, the authors show that PARP1/2 dual inhibitors may increase cancer bone metastasis through PARP2-dependent regulation of immature myeloid cells, and cause bone loss through PARP1/2-dependent regulation of osteoclasts.
- Hao Zuo
- , Dengbao Yang
- & Yihong Wan
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Article
| Open AccessMetastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs
How cancer cells engage the microenvironment to establish metastasis is poorly understood. Here, the authors show that CXCR3-expressing breast cancer cells secrete IL-1 to induce a paracrine crosstalk with fibroblasts in the lung, which involves CXCL9/10 production and results in colonization of the lung.
- Maren Pein
- , Jacob Insua-Rodríguez
- & Thordur Oskarsson
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Article
| Open AccessImmunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer
A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.
- Anniina Färkkilä
- , Doga C. Gulhan
- & Panagiotis A. Konstantinopoulos
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Article
| Open AccessCancer associated fibroblast FAK regulates malignant cell metabolism
Cancer associated fibroblasts (CAFs) have been suggested to regulate cancer cell metabolism, but the mechanisms are not completely elucidated. Here, the authors show that low FAK expression in stromal cells correlates with poor prognosis in breast and pancreatic cancer patients and that FAK-silencing in CAFs promotes tumourigenesis by the paracrine regulation of cancer cell metabolism.
- Fevzi Demircioglu
- , Jun Wang
- & Kairbaan Hodivala-Dilke
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Article
| Open AccessDivergent mutational processes distinguish hypoxic and normoxic tumours
Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.
- Vinayak Bhandari
- , Constance H. Li
- & Christian von Mering
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Article
| Open AccessTargeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties
The cytoplasmic protein FROUNT can bind to chemokine receptors and enhance chemokine signalling. Here, the authors show that inhibiting FROUNT in macrophages either by knockdown of the gene or using the anti-alcoholism drug disulfiram, results in a reduction in tumour growth.
- Yuya Terashima
- , Etsuko Toda
- & Kouji Matsushima
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Article
| Open AccessDual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors
The exclusion of cytotoxic T cells remains an important barrier to the efficacy of immunotherapies. Here the authors demonstrate that the combination anti-fibrosis agents and immune-enhanced cytokines can enhance T cell infiltration in a mouse model of pancreatic cancer.
- Yukun Huang
- , Yu Chen
- & Jun Chen
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Article
| Open AccessCD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint
Our understanding on how CAFs can be activated to support tumour progression is still limited. Here, the authors demonstrate that adenosine produced in the tumour microenvironment can enhance the expression of CD73 in CAFs ultimately driving CD8 T-Cell suppression and tumour growth.
- Miao Yu
- , Gang Guo
- & Yan Cui
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Article
| Open AccessSingle-cell analysis reveals new evolutionary complexity in uveal melanoma
Uveal melanoma is highly metastatic and unresponsive to checkpoint immunotherapy. Here, the authors present single-cell transcriptomics of 59,915 cells in 8 primary and 3 metastatic samples, highlighting the diversity of the tumour microenvironment.
- Michael A. Durante
- , Daniel A. Rodriguez
- & J. William Harbour
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Article
| Open AccessTGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells
The tumour microenvironment is known to have an acidic pH but how this influences cancer cell phenotype is unclear. Here, the authors show that tumour cells upregulate TGF-β2 under acidosis, which leads to the increased formation of lipid droplets allowing for invasiveness and metastases.
- Cyril Corbet
- , Estelle Bastien
- & Olivier Feron
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Article
| Open AccessCancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms
Cancer associated fibroblasts are known to promote the progression of cancer. Here, the authors show that two particular subsets of cancer associated fibroblasts induce metastasis but work via distinct mechanisms including, chemokine signalling and Notch signalling.
- Floriane Pelon
- , Brigitte Bourachot
- & Fatima Mechta-Grigoriou
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Article
| Open AccessFate-mapping post-hypoxic tumor cells reveals a ROS-resistant phenotype that promotes metastasis
Hypoxia is known to promote tumor progression. Here, the authors evaluate hypoxic cells using a fate mapping approach and identify a distinct gene expression profile of cells exposed to intratumoral hypoxia and show that post-hypoxic tumor cells have an ROS-resistant phenotype enabling metastasis in vivo.
- Inês Godet
- , Yu Jung Shin
- & Daniele M. Gilkes
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Article
| Open AccessThe TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer
In the treatment of pancreatic ductal adenocarcinoma (PDAC), comorbidities such as cachexia limit quality of life and survival. Here, the authors show TLR7/8 agonist R848 remodels host and tumour immune responses, promoting survival and attenuating cachexia in murine models of PDAC.
- Katherine A. Michaelis
- , Mason A. Norgard
- & Daniel L. Marks
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Article
| Open AccessTranscriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease
Multiple myeloma is a cancer of the bone marrow that can induce bone disease. Here, the authors profile the transcriptome of bone-lining cells and find a targetable role of bone morphogenetic protein (BMP) signalling in myeloma-induced bone-disease
- Sarah Gooding
- , Sam W. Z. Olechnowicz
- & Claire M. Edwards
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Article
| Open AccessNLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis
Cancer associated fibroblasts (CAFs) are known to promote pro-tumorigenic inflammation. Here, the authors show that CAFs sense tissue damage and activate NLRP3 inflammasome and pro-inflammatory IL-1β secretion, and CAF-derived inflammasome signalling promotes breast tumour growth and metastasis.
- Nour Ershaid
- , Yoray Sharon
- & Neta Erez
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Article
| Open AccessB cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma
The regulation of tumor inflammation is incompletely understood and the role of B cells is unclear. Here, the authors show that a specific subtype of B cells is induced in melanoma and required to recruit T lymphocytes and elicit inflammation.
- Johannes Griss
- , Wolfgang Bauer
- & Stephan N. Wagner
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Article
| Open AccessDistinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma
Lung adenocarcinomas frequently harbour KRAS mutations, of which a subset are characterized by co-mutation of KEAP1. Here the authors show, in mice, that KrasG12D mutant tumours are metabolically distinct, with a bronchiolar cell-of-origin.
- Sarah A. Best
- , Sheryl Ding
- & Kate D. Sutherland
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Article
| Open AccessMacrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry
Tumor associated macrophages are functionally and phenotypically heterogeneous. Here the authors describe the spatial distribution of distinct macrophage populations within regions of gastric cancer and probe their associations with clinical outcomes, gene signatures and PDL1 expression.
- Yu-Kuan Huang
- , Minyu Wang
- & Alex Boussioutas
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Article
| Open AccessBlood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy
Glioma therapy with checkpoint inhibitors has limited blood–brain barrier (BBB) penetration and therapeutic effects. Here, the authors develop nanopolymer-conjugated checkpoint inhibitors and show their trans-BBB delivery and anti-glioma efficacy.
- Anna Galstyan
- , Janet L. Markman
- & Julia Y. Ljubimova
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Comment
| Open AccessMicroenvironment meets lineage complexity in junctional tumorigenesis
Using a sensitizing genetic model, Moon and colleagues provide compelling data for a determinant role of microenvironment in tumorigenesis, and lend support to the notion that such influences can be pharmacologically dampened to reduce the onset of cancers.
- Wa Xian
- & Frank McKeon
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Article
| Open AccessSingle-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer
The benefit of combined CDK4/6 and anti-HER2 therapy in breast cancer is limited due to acquired resistance. Here, the authors perform single-cell analysis and show an immature myeloid cell population to infiltrate resistant tumors, and that combined cabozantinib and checkpoint therapy overcome this resistance with a sustained efficacy.
- Qingfei Wang
- , Ian H. Guldner
- & Siyuan Zhang
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Article
| Open AccessCAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.
- Claire Vennin
- , Pauline Mélénec
- & Paul Timpson
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Article
| Open AccessTargeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death
Reactive oxygen species induced by endoplasmic reitculum stress can be exploited for cancer therapy. Here, nanoparticles are targetted to the endoplasmic reticulum and, when accompanied by PDT, produce stress resulting in calreticulin exposure on the cell surface, which activates dendritic cells.
- Wei Li
- , Jie Yang
- & Jian You
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Article
| Open AccessBioinspired lipoproteins-mediated photothermia remodels tumor stroma to improve cancer cell accessibility of second nanoparticles
The stromal cells and extracellular matrix hamper nanoparticle access to cancer cells and their anti-cancer efficacy. Here, the authors report a bioinspired lipoprotein (bLP) for photothermal remodelling of tumour stroma and show this to improve subsequent bLP accessibility to cancer cells.
- Tao Tan
- , Haiyan Hu
- & Yaping Li
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Article
| Open AccessA ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours
In epithelial cells Zeb1 is involved in the epithelial to mesenchymal transition. In this study, the authors show in a mouse model of breast cancer, that Zeb1 expression in stromal cells is required for tumour formation and metastasis.
- Rong Fu
- , Chen-Feng Han
- & Zhao-Qiu Wu
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Article
| Open AccessProbing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy
Prodrug-based self-assembled nanoparticles have emerged as an efficient drug delivery system (DDS) for cancer therapy. Here, the authors show that the type of bond in prodrug assemblies influences the efficiency of the DDS on several different levels.
- Bingjun Sun
- , Cong Luo
- & Jin Sun
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Article
| Open AccessLandscape of transcriptomic interactions between breast cancer and its microenvironment
The transcriptomic profile of tumour-adjacent cells provides important information about tumour context but its clinical utility is unclear. Here, in breast cancer, Fox et al. show that the mRNA abundances of tumour and tumour-adjacent cells hold prognostic information.
- Natalie S. Fox
- , Syed Haider
- & Paul C. Boutros
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Article
| Open AccessRelaxin gene delivery mitigates liver metastasis and synergizes with check point therapy
Activated hepatic stellate cells are associated with fibrosis and liver metastases. Here, the authors identify an endogenous role of relaxin in regulating the activation of hepatic stellate cells and report nanoparticle-mediated relaxin gene therapy to mitigate fibrosis and liver metastasis.
- Mengying Hu
- , Ying Wang
- & Leaf Huang
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Article
| Open AccessIL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization
Mast cells within the tumor microenvironment have controversial roles. Here, the authors show, using genetic mouse models, that in gastric cancer, mast cells at the periphery of the tumors are activated via cancer cell produced-IL33 and promote tumorigenesis by recruiting macrophages within the tumors.
- Moritz F. Eissmann
- , Christine Dijkstra
- & Matthias Ernst
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Article
| Open AccessExploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence
Senescence induction is known to induce stable proliferation arrest. Here, the authors show that sustained PARP inhibition promotes a reversible p53-independent senescence, and that PARP inhibition is synthetic lethal when combined with senolytic agents in pre-clinical models of ovarian and breast cancer.
- Hubert Fleury
- , Nicolas Malaquin
- & Francis Rodier
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Article
| Open AccessTumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma
Astrocytes play important roles in neuroinflammatory diseases. Here the authors characterize human glioblastoma-associated astrocytes by gene expression and demonstrate their immunosuppressive role promoted by interactions with tumor and microglia cells in an organotypic model.
- Dieter Henrik Heiland
- , Vidhya M. Ravi
- & Oliver Schnell
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Article
| Open AccessLIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy
LIF is a pleiotropic cytokine that promotes an immunosuppressive microenvironment and has critical functions in embryonic development. Here, the authors show that LIF regulates CD8+ T cell tumor infiltration in cancer by repressing CXCL19 and promoting the presence of protumoral macrophages and thatLIF inhibition, via neutralizing antibodies, promotes T cell infiltration and synergizes with immune checkpoint inhbitors resulting in tumor regression and immunological memory.
- Mónica Pascual-García
- , Ester Bonfill-Teixidor
- & Joan Seoane
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Article
| Open AccessCaMKK2 in myeloid cells is a key regulator of the immune-suppressive microenvironment in breast cancer
Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) is highly expressed in several cancers. Here the authors investigate the role of CaMKK2 expression in the tumour microenvironment and show that CaMKK2 expression in tumour-associated macrophages promotes tumour growth by suppressing T cell anti-tumour activity.
- Luigi Racioppi
- , Erik R. Nelson
- & Donald P. McDonnell
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Article
| Open AccessCollagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung
Collagen is a dynamic component of both the tumor and metastatic niche. Here, the authors show that airway smooth muscle cells are a collagen III rich niche bladder cancer cells expressing CD167a, and Stat3 is a downstream target for abrogating these collagen III/CD167a-driven metastatic foci.
- Yu-Cheng Lee
- , Antonina V. Kurtova
- & Keith Syson Chan
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Article
| Open AccessYAP-independent mechanotransduction drives breast cancer progression
The transcriptional regulator YAP is regarded as the universal mechanotransducer, largely from 2D culture studies. Here the authors show that in breast cancer patient tissues and cells in 3D culture, mechanical signals are transduced independently of YAP, questioning YAP as a therapeutic target.
- Joanna Y. Lee
- , Jessica K. Chang
- & Ovijit Chaudhuri
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Article
| Open AccessImmunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors
Nanoparticles can stimulate tumour microenvironment to promote anti-tumour immunity. Here, the authors show that the combination of delivering drugs by a nanoscale coordination polymer and anti-PD-L1 is synergistic in treating murine colorectal cancer.
- Xiaopin Duan
- , Christina Chan
- & Wenbin Lin