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| Open AccessThe RNF214-TEAD-YAP signaling axis promotes hepatocellular carcinoma progression via TEAD ubiquitylation
RNF214 ubiquitin ligase is understudied. Here the authors show RNF214 promotes hepatocellular carcinoma progression by inducing non-proteolytic ubiquitylation of TEADs and activating YAP signaling pathway.
- Mengjia Lin
- , Xiaoyun Zheng
- & Jianping Jin
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Article
| Open AccessFBXO7 ubiquitinates PRMT1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma
How serine synthesis is regulated in cancer remains to be further explored. Here the authors identify FBXO7, an E3 ubiquitin ligase, inhibits serine synthesis in hepatocellular carcinoma by promoting ubiquitination and degradation of PRMT1 methyltransferase.
- Li Luo
- , Xingyun Wu
- & Kui Wang
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Article
| Open AccessZebrafish Avatar-test forecasts clinical response to chemotherapy in patients with colorectal cancer
Zebrafish patient-derived xenograft models (zAvatar) can be used to study cancer biology as well as to predict patient clinical outcomes and response to therapies. Here, in a cohort of 55 patients with colorectal cancer, the authors report that the zAvatar-test can predict response to chemotherapy and clinical outcome with 91% accuracy.
- Bruna Costa
- , Marta F. Estrada
- & Rita Fior
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Article
| Open AccessZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression
The relevance of post-translational modifications in pancreatic cancer remains insufficiently explored. Here, the authors report that ZDHHC20-mediated S-Palmitoylation of the m6A reader YTHDF3 stabilizes MYC mRNA to promote the progression of KRAS-mutant pancreatic cancer.
- Huan Zhang
- , Yan Sun
- & Xin Jin
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Article
| Open AccessRobotic versus laparoscopic distal gastrectomy for resectable gastric cancer: a randomized phase 2 trial
Robotic surgery has been demonstrated to improve short-term outcomes for patients with gastric cancer who received a gastrectomy, but the long-term effects are less clear. Here, the authors report the survival outcomes of their phase 2 randomized controlled trial comparing robotic to laparoscopic distal gastrectomy in patients with resectable gastric cancer.
- Jun Lu
- , Bin-bin Xu
- & Chang-Ming Huang
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Article
| Open AccessStatin prevents cancer development in chronic inflammation by blocking interleukin 33 expression
Interleukin-33 (IL-33) is a master initiator of cancer-prone chronic inflammation. Here, the authors show that TLR3/4-TBK1-IRF3 pathway activation induces IL-33, and the cholesterol-lowering drug, statin, blocks this pathway to suppress chronic inflammation and its cancer sequela.
- Jong Ho Park
- , Mahsa Mortaja
- & Shadmehr Demehri
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Article
| Open AccessDeterminants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci
The role of non-coding mutations in cancer progression and immune evasion needs to be further explored. Here, the authors investigate the potential of common somatic and germline 3′ untranslated region variants in predicting response to immunotherapy in gastric patients.
- Christos Miliotis
- , Yuling Ma
- & Ioannis S. Vlachos
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Article
| Open AccessMultiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer
Intratumoral heterogeneity has been documented in multiple cancer types, and can be linked to treatment resistance. Here, the authors analyse multiregional samples from colorectal cancers and show gene expression subtypes which are less vulnerable to heterogeneity and may partly contribute to differential patient survival.
- Jonas Langerud
- , Ina A. Eilertsen
- & Anita Sveen
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Article
| Open AccessTryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis
Amino acids availability is normally a limitation for protein synthesis and can determine cancer progression and therapy response. Here, the authors show that MYC-associated cancer has a dependency on tryptophan not because of translation regulation, but Indole 3-Pyruvate synthesis.
- Niranjan Venkateswaran
- , Roy Garcia
- & Maralice Conacci-Sorrell
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| Open AccessTargeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer
The ability of anti-cancer therapies such as radiotherapy, chemotherapy and immunotherapy to induce ferroptosis has been linked to their efficacy. Here, the authors demonstrate that SOX13 promotes ferroptosis-resistance via transactivation of SCAF1, identifying SOX13 as a targeted therapeutic vulnerability in gastric cancer.
- Hui Yang
- , Qingqing Li
- & Mingzhe Ma
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Article
| Open AccessJag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool
Dysregulation of basal progenitor cells induces esophageal tumorigenesis but the underlying mechanism is less explored. Here, the authors show that Jag1/2 deficiency promotes expansion of basal progenitor cells, leading to reduced squamous epithelial differentiation and enhanced formation of squamous cell carcinoma in the foregut.
- Haidi Huang
- , Yu Jiang
- & Yongchun Zhang
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Article
| Open AccessCEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials
Cibisatamab is a T-cell bispecific antibody targeting the carcinoembryonic antigen (CEA) on tumor cells and CD3 epsilon chain on T cells. Here the authors report the results of two clinical trials of cibisatamab as monotherapy (NCT02324257) and in combination with atezolizumab (anti-PD-L1; NCT02650713) in patients with CEA-positive solid tumors.
- Neil H. Segal
- , Ignacio Melero
- & Guillem Argilés
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Article
| Open AccessDisentangling oncogenic amplicons in esophageal adenocarcinoma
Esophageal adenocarcinoma is characterised by frequent amplifications in oncogenes. Here, the authors use short- and long-read sequencing approaches to analyze primary tumor samples and tumour-derived organoids and to investigate the mechanisms underlying complex amplifications.
- Alvin Wei Tian Ng
- , Dylan Peter McClurg
- & Rebecca C. Fitzgerald
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| Open AccessNetwork-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis
Aberrant signalling pathway activity is relevant for tumour growth and resistance to therapy, but remains hard to understand and target. Here, the authors develop VESPA, a phosphoproteomics-based machine learning algorithm that can elucidate response and adaptation to drug perturbations in cancer signalling pathways.
- George Rosenberger
- , Wenxue Li
- & Andrea Califano
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Article
| Open AccessFGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma
FGFR inhibitors (FGFRi) benefit patients with FGFR2-fusion positive intrahepatic cholangiocarcinoma (ICC) but depth and duration of response is often limited. Here, the authors demonstrate that oncogenic FGFR2 signaling promotes a glycolytic phenotype, which is blocked by FGFRi, resulting in a targetable dependence on mitochondrial metabolism.
- Yuanli Zhen
- , Kai Liu
- & Nabeel Bardeesy
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Article
| Open AccessMultimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions
Esophageal squamous cell carcinoma is most commonly detected at a late stage, which limits survival and treatment options. Here, the authors utilise whole genome bisulfite sequencing to create a cfDNA framework to detect cfDNA methylation, copy number variants and fragmentation.
- Jiaqi Liu
- , Lijun Dai
- & Zhihua Liu
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Article
| Open AccessMitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression
The interaction between colon cancer cells and colonic epithelial cells (CECs) is critical yet not well-known. Here, the authors show that tumor extracellular vesicles mediate mitochondrial DNA transfer to CECs, initiating mitochondrial activation and RelA-induced TGFβ1 expression, leading to tumor progression.
- Bingjie Guan
- , Youdong Liu
- & Dongwang Yan
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Article
| Open AccessMacrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer
An inflammatory-fibrotic tumor microenvironment supports metastatic disease progression in pancreatic ductal adenocarcinoma (PDAC). Here the authors show that metastasis-infiltrating macrophages influence metastasis-associated fibroblast (MAF) heterogeneity in liver metastatic PDAC, by promoting JAK/STAT signalling pathway activation in MAFs.
- Meirion Raymant
- , Yuliana Astuti
- & Michael C. Schmid
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| Open AccessThe pRb/RBL2-E2F1/4-GCN5 axis regulates cancer stem cell formation and G0 phase entry/exit by paracrine mechanisms
Cancer stem cells (CSCs) are associated with chemoresistance and poor prognosis in multiple cancer types. Here, the authors investigate the role of secreted Wnt ligands in pancreatic and breast CSCs and identify E2F1/4-GCN5-pRb/RBL2 as a regulatory axis underlying Wnt secretion.
- Chao-Hui Chang
- , Feng Liu
- & Siim Pauklin
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Article
| Open AccessConsistent signatures in the human gut microbiome of old- and young-onset colorectal cancer
The rising incidence of young-onset sporadic colorectal cancer (yCRC) is global concern. Here, leveraging a substantial number of deep sequencing metagenomes, the authors show striking similarities in gut microbial patterns at both the taxonomic and selected gene marker levels between yCRC and old-onset CRC.
- Youwen Qin
- , Xin Tong
- & Pei-Rong Ding
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Article
| Open AccessDiet changes due to urbanization in South Africa are linked to microbiome and metabolome signatures of Westernization and colorectal cancer
Here, the authors present a comparative analysis of the diet, microbiome and metabolome of rural and urban Xhosa people in South Africa, associating urban diets with higher abundances of pro-neoplastic microbial metabolites.
- M. C. Ramaboli
- , S. Ocvirk
- & S. J. D. O’Keefe
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Article
| Open AccessMembrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells
The mechanical properties of heterogeneous cell populations in colorectal tumors and the relevance to cancer metastasis remain not fully understood. Here, the authors suggest that the variations in malignant phenotypes between LGR5-positive cancer stem cells and LGR5-negative cells could be due to their distinct mechanical phenotypes observed in vitro, determined by the membrane to cortex attachment proteins Ezrin/Radixin/Moesin.
- Sefora Conti
- , Valeria Venturini
- & Xavier Trepat
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| Open AccessNeoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial
The feasibility and efficacy of neoadjuvant immunotherapy for resectable hepatocellular carcinoma (HCC) have been previously suggested. Here the authors report the results of a phase 1b trial of neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable HCC.
- Zhongchao Li
- , Jing Liu
- & Lei Zhao
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Article
| Open AccessTumor phylogeography reveals block-shaped spatial heterogeneity and the mode of evolution in Hepatocellular Carcinoma
Hepatocellular carcinomas (HCC) present spatial intratumour heterogeneity (sITH). Here, the authors perform a genomic and phylogenetic analysis of spatially-sampled HCC tumour sections, observe block-shaped sITH, and find ongoing natural selection where ancestral and derived clones spatially compete in the same tumor.
- Xiaodong Liu
- , Ke Zhang
- & Weiwei Zhai
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Article
| Open AccessNardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer
Polo-like kinase 3 (Plk3) has a tumor suppressive role through the induction of apoptosis, however, the mechanism underlying its activation is unclear. Here, in pancreatic cancer, the authors show that activation of Plk3 is dependent on its cleavage into p41Plk3, by the metalloendopeptidase nardilysin.
- Jie Fu
- , Jianhua Ling
- & Paul J. Chiao
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Article
| Open AccessDecoding spatiotemporal transcriptional dynamics and epithelial fibroblast crosstalk during gastroesophageal junction development through single cell analysis
Elucidating the gastroesophageal junction’s development is key to comprehending its disease susceptibility. Here, the authors mapped its development, uncovering cellular diversity and interaction dynamics using advanced spatiotemporal single-cell analysis.
- Naveen Kumar
- , Pon Ganish Prakash
- & Cindrilla Chumduri
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Article
| Open AccessSingle-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma
Hepatoblastoma (HB) is the most frequent paediatric liver tumour with heterogeneous cellular phenotypes that influence clinical outcomes. Here, the authors integrate bulk, single-cell, and spatial multi-omics to characterise HB cells, and find that clonal evolution and epigenetic plasticity shape response to therapy.
- Amélie Roehrig
- , Theo Z. Hirsch
- & Eric Letouzé
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Article
| Open AccessA population-based cohort study of longitudinal change of high-density lipoprotein cholesterol impact on gastrointestinal cancer risk
High-density Lipoprotein Cholesterol (HDL-C) levels have been associated with cancer. Here, the authors show the association between longitudinal changes of HDL-C and risk of gastrointestinal cancer in a patients.
- Su Youn Nam
- , Junwoo Jo
- & Chang-Min Cho
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Article
| Open AccessIdentification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms
The current stratification of Intraductal Papillary Mucinous Neoplasms (IPMN) is based on clinical and histological features rather than molecular ones. Here, the authors use spatial transcriptomics to characterise IPMN patient samples, and identify markers associated with progression to pancreatic cancer.
- Antonio Agostini
- , Geny Piro
- & Carmine Carbone
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Article
| Open AccessCancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma
Distinct genetic mutations can shape the tumor immune microenvironment. Here the authors generate preclinical mouse models of hepatocellular carcinoma bearing clinically-relevant oncogenic driver combinations, identifying myeloid cell-centric exploitable therapeutic vulnerabilities.
- Christel F. A. Ramirez
- , Daniel Taranto
- & Leila Akkari
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Article
| Open AccessThe EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression
Eukaryotic initiation translation factor 3 subunit h (EIF3H) possesses an alternative “moonlighting” function of deubiquitinase, while its role in colorectal carcinogenesis remains to be explored. Here the authors show that EIF3H deubiquitinates and stabilizes HAX1, which enhances RAF-MEK-ERK signaling to promote colorectal tumor growth and metastasis.
- Huilin Jin
- , Xiaoling Huang
- & Mong-Hong Lee
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Article
| Open AccessCombined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer
The MAPK pathway is an important therapeutic target in pancreatic ductal adenocarcinoma (PDAC), but success is limited by pathway reactivation, which drives resistance. Here, the authors investigate the mechanism underlying HER2-reactivation post KRAS-MAPK inhibition, identifying combination of MAPK and HER2 inhibition as a therapeutic strategy.
- Ashenafi Bulle
- , Peng Liu
- & Kian-Huat Lim
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Article
| Open AccessNMR and MS reveal characteristic metabolome atlas and optimize esophageal squamous cell carcinoma early detection
Metabolic changes often occur during the early stages of cancer development. Here, the authors develop metabolomics signatures from tissues, pre- and post-operative sera and urines in esophageal squamous cell carcinoma, which may aid in early diagnosis.
- Yan Zhao
- , Changchun Ma
- & Yan Lin
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| Open AccessIdentifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system
Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer. Here, authors develop a dual endogenous reporter system to identify functional regulators of aberrant stem cell and differentiation programs, showing that SMARCB1 restricts differentiation, and nominating other regulators with therapeutic potential.
- Sandor Spisak
- , David Chen
- & Nilay S. Sethi
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Article
| Open AccessDelivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models
Therapeutic options for pancreatic ductal adenocarcinoma (PDAC) are limited. Here the authors report the characterization of a CEACAM6-targeting antibody drug conjugate loaded with a BET protein degrader, showing antitumour activity in PDAC preclinical models.
- Youya Nakazawa
- , Masayuki Miyano
- & Akihito Machinaga
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Article
| Open AccessEnabling large-scale screening of Barrett’s esophagus using weakly supervised deep learning in histopathology
Diagnosis of Barrett’s esophagus depends on pathologist assessment of stained slides. Here, the authors utilise a deep learning approach to prioritize potential cases using diagnostic labels in two datasets, with the aim to improve Barrett’s screening capacity.
- Kenza Bouzid
- , Harshita Sharma
- & Javier Alvarez-Valle
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Article
| Open AccessThe phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial
Bavituximab is a genetically engineered IgG1 chimeric antibody that targets phosphatidylserine. Here the authors report the results of a single-arm phase 2 trial of bavituximab in combination with pembrolizumab (anti-PD1) for patients with unresectable hepatocellular carcinoma.
- David Hsiehchen
- , Muhammad S. Beg
- & Adam C. Yopp
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Article
| Open AccessThe transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism
Cancer cells adapt to changes in metabolism to ensure their survival. Here the authors show that glucose responsive transcription factor ChREBP reprograms liver cancer metabolism in part via enhancing the PI3K/AKT signaling.
- Emmanuel Benichou
- , Bolaji Seffou
- & Renaud Dentin
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Article
| Open AccessSerum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma
The reasons for why hepatocellular carcinoma (HCC) is unresponsive to anti-PD-1 inhibition in some patients is not fully understood. Here the authors use human samples and mice tumour models to implicate serum amyloid A and STAT3 signalling involvement in the resistance to anti-PD1 immunotherapy in HCC.
- Meng He
- , Yongxiang Liu
- & Ning Lyu
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Article
| Open AccessFusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15
Several studies have shown that Fusobacterium nucleatum aggravates colorectal cancer (CRC) development and chemoresistance. Here the authors show that F. nucleatum is enriched preferentially in patients with KRAS p.G12D mutant CRC and that it promotes colorectal tumorigenesis in preclinical models by binding DHX15 on tumor cells.
- Huiyuan Zhu
- , Man Li
- & Huanlong Qin
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Article
| Open AccessMetabolomic machine learning predictor for diagnosis and prognosis of gastric cancer
Gastric cancer detection by endoscopy is intrusive and time-consuming, and early detection is key to improving survival. Here, the authors propose a metabolite-based model to enable early detection.
- Yangzi Chen
- , Bohong Wang
- & Zeping Hu
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Article
| Open AccessExosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma
The behavior of exosomes in vivo is not completely elucidated. Here the authors develop a genetically engineered mouse model (ExoBow) to trace the distribution of exosomes, showing local and inter-organ communication networks, either specific or shared between healthy pancreas and pancreatic ductal adenocarcinoma.
- Bárbara Adem
- , Nuno Bastos
- & Sonia A. Melo
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Article
| Open AccessPlasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma
Acquired resistance to immune checkpoint inhibitors represents an important clinical challenge. Here, in a pancreatic ductal adenocarcinoma model of acquired resistance to immunotherapy, the authors show that plasticity-induced repression of Irf6 is associated with tumor cell-intrinsic resistance to cytotoxic T-cell activity.
- Il-Kyu Kim
- , Mark S. Diamond
- & Ben Z. Stanger
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Article
| Open AccessClinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort
CAMILLA is a basket trial evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Here, the authors present the result of the phase II in the colorectal cohort.
- Anwaar Saeed
- , Robin Park
- & Azhar Saeed
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Article
| Open AccessPAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma
MYC drives S-phase progression and immune invasion in pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms are not fully understood. Here, the authors show that the transcription elongation complex PAF1c controls the competition of different gene sets for RNA polymerase and elongation factors to regulate these MYC-associated mechanisms in PDAC.
- Abdallah Gaballa
- , Anneli Gebhardt-Wolf
- & Martin Eilers
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Article
| Open AccessTissue-location-specific transcription programs drive tumor dependencies in colon cancer
Cancers of the same tissue type are characterized with different molecular features depending on anatomical location. Here, the authors show that proximal and distal colon stem cells have distinct transcriptional programs mediated by the transcription factor CDX2, with differential roles in colon cancers based on anatomical location.
- Lijing Yang
- , Lei Tu
- & Hariharan Easwaran
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Article
| Open AccessHKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression
Aberrant expression of the human hexokinase HKDC1 has been observed in patients with cancer. Here the authors report that HKDC1 expression is associated with hepatocellular carcinoma progression and PD-L1 mediated immune evasion.
- Yi Zhang
- , Mingjie Wang
- & Ping Gao
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Article
| Open AccessThe molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma
The application of fibroblast growth factor receptor (FGFR)−2 selective tyrosine kinase inhibitors (TKIs) in cholangiocarcinoma (CCA) with FGFR2 fusions has been reported to lead to mutations in the kinase domain of FGFR2.
Here, the authors report that non-selective TKI, lenvatinib may be an alternative in case of insurmountable side effects to specific FGFR inhibitors or to overcome and delay the development of resistance mediating FGFR2 mutations.
- Stephan Spahn
- , Fabian Kleinhenz
- & Michael Bitzer
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Article
| Open AccessTargeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma
Immune checkpoint inhibitors have now been approved for the treatment of advanced hepatocellular carcinoma (HCC), however only a minority of patients appear to benefit. Here the authors report that RNase1 levels predict response to nivolumab (anti-PD1) in patients with HCC and that RNase 1 overexpression correlates with an immunosuppressive tumor microenvironment in HCC preclinical models.
- Chunxiao Liu
- , Chenhao Zhou
- & Mien-Chie Hung