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| Open AccessIdentification 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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Article
| Open AccessLysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase
Novel strategies are needed to overcome chemotherapy resistance. Here the authors report chemotherapy induces the phosphorylation of Lysyl oxidase-like 3, which in turn stabilizes dihydroorotate dehydrogenase (DHODH) and that DHODH inhibitor sensitizes tumor cells to oxaliplatin treatment by inducing ferroptosis in liver cancer.
- Meixiao Zhan
- , Yufeng Ding
- & Xiongjun Wang
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| Open AccessTowards evidence-based response criteria for cancer immunotherapy
Early detection of immunotherapy-induced tumor response is of major benefit for patients but can be complicated by therapy-induced pseudoprogression. A consensus guideline-iRECIST- was developed as a modification of Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). Here we describe which next steps are required to test its validity and how novel approaches for response criteria might be developed and included.
- Elena Garralda
- , Scott A. Laurie
- & Elisabeth G. E. de Vries
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Article
| Open AccessSingle-cell analysis of gastric signet ring cell carcinoma reveals cytological and immune microenvironment features
The tumour microenvironment in signet ring cell carcinoma (SRCC) remains to be characterised. Here, the authors perform single-cell RNA sequencing and reveal distinct features compared to moderately/poorly differentiated adenocarcinoma.
- Weizhu Zhao
- , Yanfei Jia
- & Jie Chai
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Article
| Open AccessDurvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin
Single immune checkpoint blockade has shown limited activity in patients with neuroendocrine neoplasms (NENs). Here the authors report the results of a phase II clinical trial of durvalumab (anti-PD-L1) and tremelimumab (anti CTLA-4) in patients with advanced NENs of gastroenteropancreatic and lung origin.
- J. Capdevila
- , J. Hernando
- & J. L. Manzano
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Article
| Open AccessMicrobial synthesis of Prussian blue for potentiating checkpoint blockade immunotherapy
Prussian blue has been used as a photothermal agent for cancer therapy. Here the authors describe the production of Prussian blue nanoparticles from S. oneidensis MR-1 bacteria and show that a Prussian blue-based mitochondria-targeting nanoplatform potentiates response to immune checkpoint blockade.
- Dongdong Wang
- , Jiawei Liu
- & Yanli Zhao
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Article
| Open AccessDasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia
Despite playing a central role the treatment of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), resistance to glucocorticoids remains a major obstacle. Here, the authors identify activation of PI3K/mTOR and CREB pathways as a driver of GC-resistance in BCP-ALL and restore sensitivity using the multi kinase inhibitor, dasatinib.
- Jolanda Sarno
- , Pablo Domizi
- & Kara L. Davis
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Article
| Open AccessAlanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss
Cancers with concomitant SMARCA4/2 deficiencies are often resistant to chemotherapies and confer a poor prognosis. Here, the authors identify a metabolic dependency of these tumours on glutamine as an energy source and, using multiple approaches, demonstrate the efficacy of therapeutically targeting this vulnerability.
- Xianbing Zhu
- , Zheng Fu
- & Sidong Huang
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Article
| Open AccessADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer
Resistance to 5-fluorouracil and cisplatin (5FU + CDDP) presents a major issue in patients with gastric cancer. Here, the authors establish 5FU + CDDP resistant intestinal gastric cancer patient-derived organoids and identify JAK/STAT-ADAR1 altered lipid metabolism as a regulator of chemoresistance.
- Tin-Lok Wong
- , Jia-Jian Loh
- & Stephanie Ma
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Article
| Open AccessERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy
Ubiquitination and deubiquitination processes regulate the stability of PD-1, affecting T cell biology. Here the authors identify the ubiquitin-specific protease 5 (USP5) as a deubiquitinase for PD-1 and show that USP5 inhibition in combination with a MEK inhibitor or anti-CTLA-4 could promote anti-tumor immune responses in preclinical models.
- Xiangling Xiao
- , Jie Shi
- & Jinfang Zhang
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Article
| Open AccessClinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma
Dual PD-1 and CTLA-4 checkpoint blockade has proven effective in several cancer types. Here the authors report the results of a clinical trial of anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) in patients with recurrent/metastatic EBV-positive nasopharyngeal carcinoma.
- Darren Wan-Teck Lim
- , Hsiang-Fong Kao
- & N. Gopalakrishna Iyer
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Article
| Open Accessp140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response
The p140Cap adaptor protein is a tumour suppressor associated with improved prognosis in breast cancer. Here, the authors identify a role for p140Cap in preventing the immunosuppressive and pro-tumour function of polymorphonuclear myeloid-derived suppressor cells via downmodulation of the β-Catenin/Tumor Initiating Cells/G-CSF axi
- Vincenzo Salemme
- , Mauro Vedelago
- & Paola Defilippi
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Article
| Open AccessPhase II trial of neoadjuvant sitravatinib plus nivolumab in patients undergoing nephrectomy for locally advanced clear cell renal cell carcinoma
In patients with locally advanced clear cell renal cell carcinoma (ccRCC), neoadjuvant therapy prior to curative nephrectomy has been shown to improve patient outcomes. Here, the authors report the safety and radiological efficacy of a phase II clinical trial investigating neoadjuvant sitravatinib (tyrosine kinase inhibitor) and nivolumab (PD-1 inhibitor) in locally advanced ccRCC.
- Jose A. Karam
- , Pavlos Msaouel
- & Christopher G. Wood
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Article
| Open AccessSkin basal cell carcinomas assemble a pro-tumorigenic spatially organized and self-propagating Trem2+ myeloid niche
Tumor microenvironment elements can influence tumor state, including in skin basal cell carcinomas. Here the authors show that spatially organized and self-propagating TREM2+ tumor associated macrophages promote Ly6D- tumor cell proliferation via secretion of oncostatin M.
- Daniel Haensel
- , Bence Daniel
- & Anthony E. Oro
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Article
| Open AccessHepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis
Activated hepatic stellate cells (aHSC) promote hepatocellular carcinoma (HCC). Here the authors show that selective ablation of stearoyl CoA desaturase-2 in aHSC suppresses leukotriene B4 receptor 2-dependent nuclear β-catenin signaling, preventing liver tumorigenesis.
- Sonal Sinha
- , Satoka Aizawa
- & Hidekazu Tsukamoto
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Article
| Open AccessIntegrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence
Genomic landscape studies of malignant germ cell tumors (GCTs) that occur in children, adolescents and young adults are limited. Here the authors perform multi-omics profiling of different types of GCTs across the age spectrum from 0–24 years and show that WNT signalling pathway is activated in GCTs and is associated with poor clinical outcomes.
- Lin Xu
- , Joshua L. Pierce
- & James F. Amatruda
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Article
| Open AccessType 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
| Open AccessKK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer
The presence of breast cancer stem cells is associated with therapy resistance in patients with triple-negative breast cancer (TNBC). Here, the authors identify KK-LC-1-mediated YAP signaling as a driver of TNBC stemness and develop a therapeutic molecule to target this axis in preclinical models of TNBC.
- Jiawen Bu
- , Yixiao Zhang
- & Caigang Liu
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Article
| Open AccessGenomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients
Xeroderma pigmentosum (XP) is a rare genetic disorder that is associated with a higher risk of skin cancer. Here, the authors analyse the genomes of skin cancers from patients across five different XP groups, revealing genetic and molecular factors related to the mutational profile and UV-related mutagenesis in XP.
- Andrey A. Yurchenko
- , Fatemeh Rajabi
- & Sergey I. Nikolaev
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Article
| Open AccessMetabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma
The molecular mechanisms underlying MYC overexpression in group 3 medulloblastoma remain to be explored. Here, the authors highlight the involvement of the mitochondrial pyruvate carrier- SOD2 signalling pathway in the regulation of MYC protein abundance.
- Emma Martell
- , Helgi Kuzmychova
- & Tanveer Sharif
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Article
| Open AccessDNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC
DNA polymerase 1 (POLD1) has an important role in DNA damage repair and is frequently upregulated in cancer. Here, the authors report a non-canonical role of POLD1 wherein it stabilises MYC protein, creating a positive feedback loop with POLD1 expression and driving bladder cancer progression and metastasis.
- Yejinpeng Wang
- , Lingao Ju
- & Xinghuan Wang
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Article
| Open AccessAnti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4
IgE antibodies targeting cancer antigens can be used for immunotherapy. Here the authors present an IgE antibody targeting the melanoma-associated antigen, chondroitin sulphate proteoglycan 4, that recognises human melanoma, stimulates tumour cell cytotoxicity, and restricts tumour growth in humanised mouse models.
- Jitesh Chauhan
- , Melanie Grandits
- & Heather J. Bax
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Article
| Open AccessImmune cellular patterns of distribution affect outcomes of patients with non-small cell lung cancer
The spatial distribution of cellular compartments within the tumour microenvironment in non-small cell lung cancer (NSCLC) remains to be investigated. Here, the authors identify distinct cell populations of tumour cells and tumour-associated immune cell phenotypes with different spatial distributions in NSCLC.
- Edwin Roger Parra
- , Jiexin Zhang
- & Ignacio Ivan Wistuba
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Article
| Open AccessMetabolomic differentiation of benign vs malignant pulmonary nodules with high specificity via high-resolution mass spectrometry analysis of patient sera
Detection of lung adenocarcinoma through serum sampling could be an alternative to CT scanning. Here, the authors use global metabolomics to create a 27 metabolite signature, which showed accuracy in detection in an external validation cohort.
- Yao Yao
- , Xueping Wang
- & Yumin Hu
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Article
| Open AccessHAPLN1 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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Article
| Open AccessIn silico cancer immunotherapy trials uncover the consequences of therapy-specific response patterns for clinical trial design and outcome
Conventional clinical trial design methods are not necessarily tailored for the unique characteristics of immunotherapies. Here the authors use late-stage in silico cancer immunotherapy trials to investigate how design decisions affect the trial outcome.
- Jeroen H. A. Creemers
- , Ankur Ankan
- & Johannes Textor
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Article
| Open Access3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma
Ependymoma is a tumor of the brain or spinal cord with the two most common and aggressive types mainly occurring in children. Here the authors employ 3D genomics and epigenomics to reveal targets for aggressive ependymoma tumors in children.
- Konstantin Okonechnikov
- , Aylin Camgöz
- & Lukas Chavez
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Article
| Open AccessSema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma
Wnt signaling is dysregulated in glioblastoma (GBM). Here the authors show that Semaphorin 3C drives Wnt signaling through Rac1-dependent β-catenin nuclear accumulation and that dual blockade of Semaphorin 3C and Wnt pathway reduces the growth of GBM in vivo.
- Jing Hao
- , Xiangzi Han
- & Jennifer S. Yu
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Article
| Open AccessTranscriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia
The CLL14 study (NCT02242942) explored the activity of obinutuzumab (anti-CD20) plus venetoclax (Bcl2 inhibitor) versus obinutuzumab plus chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL). Here the authors report the 5-year long-term results of the clinical trial and transcriptional profiles associated with response to therapies.
- Othman Al-Sawaf
- , Can Zhang
- & Kirsten Fischer
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Article
| Open AccessDistinct spatial immune microlandscapes are independently associated with outcomes in triple-negative breast cancer
The tumor immune microenvironment is an important determinant of clinical outcomes and therapeutic responses in patients with triple-negative breast cancer (TNBC). Here the authors perform digital spatial profiling of tumor tissues to characterize the spatial immunobiology of treatment-naïve TNBC.
- Jodi M. Carter
- , Saranya Chumsri
- & E. Aubrey Thompson
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Article
| Open AccessPriming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors
It has been reported that inhibition of the epigenetic regulator DNA methyltransferase 1 (DNMT1) is associated with improved response to immune checkpoint blockade (ICB). Here the authors show that conditional deletion of Dnmt1 in endothelial cells is sufficient to promote T cell infiltration, reduce tumor growth and enhance ICB response in preclinical models.
- Dae Joong Kim
- , Swetha Anandh
- & Andrew C. Dudley
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Article
| Open AccessHistopathology images predict multi-omics aberrations and prognoses in colorectal cancer patients
Histopathological analysis is an essential tool in diagnosing colorectal cancer, but is limited in predicting prognosis and molecular profiles. Here, the authors designed a machine learning-based platform to predict multi-omics profiles and prognosis from pathology images.
- Pei-Chen Tsai
- , Tsung-Hua Lee
- & Kun-Hsing Yu
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Article
| Open AccessExcessive serine from the bone marrow microenvironment impairs megakaryopoiesis and thrombopoiesis in Multiple Myeloma
The molecular mechanisms underlying the development of thrombocytopenia in multiple myeloma (MM) remain to be explored. Here, the authors show an association of thrombocytopenia with poor prognosis in MM and identify serine as a key metabolic regulator of thrombocytopenia.
- Chunmei Kuang
- , Meijuan Xia
- & Wen Zhou
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Article
| Open AccessAntimicrobial exposure is associated with decreased survival in triple-negative breast cancer
Here, in a cohort of 772 women undergoing triple-negative breast cancer (TNBC) therapy, the authors show that antimicrobial prescription during TNBC treatment associates with inferior overall and breast cancer-specific survival, in turn related to peripheral lymphocyte count and gut microbiome dysbiosis.
- Julia D. Ransohoff
- , Victor Ritter
- & Allison W. Kurian
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Article
| Open AccessInducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models
The clinical benefits of chimaeric antigen receptor (CAR) T therapy are limited by ‘on-target, off-tumour’ effects. In this study, the authors describe a strategy that promotes the recognition of antigen on tumour, but not normal, cells by combining affinity tuning with inducible interleukin-12 expression.
- Yanping Yang
- , Huan Yang
- & Moonsoo M. Jin
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Article
| Open AccessInflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis
Age related accumulation of adipocytes in the bone marrow could alter normal and leukemic haematopoiesis. Here, in fatty bone marrow (FBM) preclinical models, the authors show that inflammatory cytokines increased in the FBM, such as IL-6, promote DNMT3a driven clonal hematopoiesis.
- N. Zioni
- , A. Akhiad Bercovich
- & Liran I. Shlush
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Article
| Open AccessTargeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy
Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a highly enriched cell surface antigen expressed in prostate cancer. Here the authors describe the design of STEAP1 directed CART cells and show their antitumor activity in preclinical models of prostate cancer, also in combination with a collagen binding domain-IL-12 fusion cytokine.
- Vipul Bhatia
- , Nikhil V. Kamat
- & John K. Lee
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Article
| Open AccessHypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent allogeneic humanized mice
The development of allogeneic chimaeric antigen receptor (CAR) T cells could overcome manufacturing bottlenecks for immunotherapy. However, immune rejection reduces the persistence and efficacy of these cells. Here, the authors generate allogeneic anti-CD19 CAR T cells that can evade the immune system and provide durable anti-tumour responses.
- Xiaomeng Hu
- , Karl Manner
- & Sonja Schrepfer
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Article
| Open AccessPredicting response to enzalutamide and abiraterone in metastatic prostate cancer using whole-omics machine learning
Prostate cancer is known to have a variable response to androgen receptor signalling inhibitors. Here, the authors use machine learning to predict response to therapy from genomic, transcriptomic and clinical data.
- Anouk C. de Jong
- , Alexandra Danyi
- & Martijn P. Lolkema
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Article
| Open AccessMOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
Altered transcriptional machinery promotes aberrant self-renewal of non-stem hematopoietic progenitors. Here the authors show that AF10 fusion proteins cause aberrant self-renewal via ENL, which promotes leukemic transformation by binding to MOZ/MORF lysine acetyltransferases
- Yosuke Komata
- , Akinori Kanai
- & Akihiko Yokoyama
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Article
| Open AccessEngineering tumor-specific gene nanomedicine to recruit and activate T cells for enhanced immunotherapy
Intratumoral abundance of chemokines, such as CXCL9, is an important driver of T cell infiltration in tumors. Here the authors describe the design of a tumor-specific expression strategy to drive secretion of CXCL9 and an anti-PD-L1 scFv (αPD-L1) in the tumor microenvironment, promoting T cell recruitment and anti-tumor immune response in preclinical cancer models.
- Yue Wang
- , Shi-Kun Zhou
- & Jun Wang
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Article
| Open AccessHomologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers
Homologous recombination deficiency is linked with platinum-based chemotherapy response in triple-negative breast cancer (TNBC) but methods to clinically identify these patients are lacking. Here, using patient-derived xenografts of TNBC the authors demonstrate that shallow HRD is predictive of response to platinum-based chemotherapy.
- Petra ter Brugge
- , Sarah C. Moser
- & Elisabetta Marangoni
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Article
| Open AccessNasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction
Response rates to immunotherapies in patients with nasopharyngeal carcinoma (NPC) are still limited. Here the authors show that tumor-restricted CD70 correlates with regulatory T cell abundance and suppressive activity in NPC and that CD70 blockade improves response to anti-PD1 in preclinical models.
- Lanqi Gong
- , Jie Luo
- & Xin-Yuan Guan
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Article
| Open AccessTargeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
Resistance of FLT3-ITD acute myeloid leukaemia (AML) patients to FLT3 inhibitors (FLT3i) remains an urgent clinical challenge. Here, the authors identify C/EBPα activation as a mechanism of FLT3i resistance and therapeutically target C/EBPα activation in combination with FLT3i in preclinical models FLT3-ITD AML.
- Hanlin Wang
- , Guanghao Luo
- & Jia Li
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Article
| Open AccessEtiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication
Oncogenic gene fusions are frequent in childhood cancers but remain poorly understood and untargeted. Here, the authors identify 272 oncogenic fusions in transcriptomics data from 5190 childhood cancer patients, revealing their possible etiologies, their links with tumor progression and evolution, and their potential as therapeutic targets.
- Yanling Liu
- , Jonathon Klein
- & Xiaotu Ma
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Article
| Open AccessAn epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma
Melanocytes can de-differentiate into neural crest cell (NCC)- like states during metastatic melanoma progression. Here the authors compare DNA methylation profiles of NCCs and melanocytes, as well as primary and metastatic patient tissues and identify that DNA methylation changes of NR2F2 isoform 2 influence cell state transitions and melanoma metastatic spread.
- Veronica Davalos
- , Claudia D. Lovell
- & Eva Hernando
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Article
| Open AccessMonocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma
Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment promotes a compensatory neutrophil influx and that concomitant neutrophil inhibition is required to improve survival in GBM preclinical models.
- Zhihong Chen
- , Nishant Soni
- & Dolores Hambardzumyan
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Article
| Open AccessSmad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma
TGF-β stimulated tumor-associated neutrophils (TANs) can exert pro-tumoral functions. Here the authors show that Smad3 activation in TANs is associated with an N2-like polarization state and poor outcome in patients with non-small cell lung carcinoma and that Smad3 targeting reprograms TANs to an antitumor state suppressing tumor growth in preclinical lung cancer models.
- Jeff Yat-Fai Chung
- , Philip Chiu-Tsun Tang
- & Patrick Ming-Kuen Tang
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Article
| Open AccessAn actin filament branching surveillance system regulates cell cycle progression, cytokinesis and primary ciliogenesis
The authors find that the ciliopathy-associated protein Oral-Facial-Digital syndrome 1 functions as a class II nucleation promoting factor to drive actin filament branching, required for cell cycle progression. Interferring with this function suppresses cancer cell growth.
- Muqing Cao
- , Xiaoxiao Zou
- & Qing Zhong