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| Open AccessLow-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells
An increasing number of preclinical and clinical studies have investigated the antitumor efficacy of combined radiotherapy and immunotherapy. Here the authors report that low-dose radiotherapy enhances the antitumor effect of dual VEGFA and PD-L1 blockade in preclinical models of hepatocellular carcinoma.
- Siqi Li
- , Kun Li
- & Yang Yang
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Article
| Open AccessID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer
Inhibitor of differentiation 1 (ID1) has been described as a cancer-promoting factor and also involved in the formation of an immunosuppressive tumor microenvironment. Here the authors report that ID1-expressing tumor associated macrophages favor colorectal cancer progression by promoting cancer cell stemness and CD8+ T cell exclusion.
- Shuang Shang
- , Chen Yang
- & Fang Hua
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Article
| Open AccessIndocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial
Due to high rate of metastasis, lymphadenectomy is a cornerstone of the surgical treatment of gastric cancer however the accurate dissection of lymph nodes (LN) can be challenging. Here, the authors present the long-term outcomes of a randomised control trial investigating indocyanine green fluorescence image-guided LN retrieval in gastric cancer patients undergoing laparoscopic gastrectomy.
- Qi-Yue Chen
- , Qing Zhong
- & Chang-Ming Huang
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Article
| Open AccessValidation of MSIntuit as an AI-based pre-screening tool for MSI detection from colorectal cancer histology slides
Microsatellite instability is a known risk factor for colorectal cancer development and treatment response. Here, the authors utilise deep learning to develop MSIntuit, a pre-screening tool to detect MSI from H&E stained slides.
- Charlie Saillard
- , Rémy Dubois
- & Magali Svrcek
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Article
| Open AccessPreneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma
Paediatric liver cancer is rare, and often associated with a predisposition syndrome. Here, the authors show that 11p15.5 mosaic alteration in the liver is a pre-neoplastic lesion associated with hepatoblastoma, and spatial transcriptomics together with single-nucleus RNAseq identify a an altered zonation in the liver of these patients.
- Jill Pilet
- , Theo Z. Hirsch
- & Jessica Zucman-Rossi
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Article
| Open AccessCathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation
Bile duct tumor thrombosis (BDTT) is a complication associated with advanced hepatocellular carcinoma (HCC) which can severely limits quality of life. Here, the authors develop a spontaneous BDTT mouse model to investigate the cellular original and mechanism underlying the formation of BDTT.
- Lei-Bo Xu
- , Yu-Fei Qin
- & Ping-Pui Wong
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Article
| Open AccessCyclic fasting bolsters cholesterol biosynthesis inhibitors’ anticancer activity
Nutritional stress induced by short-term dietary restriction has been shown to alter the activity of some anti-tumour drugs. Here, the authors demonstrate that periodic fasting enhances the anti-tumour effect of cholesterol biosynthesis inhibitors via decreased AKT-STAT3 signaling and oxidative phosphorylation.
- Amr Khalifa
- , Ana Guijarro
- & Alessio Nencioni
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Article
| Open AccessThe Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium
Crosstalk between tumor cells and the microenvironment is essential for tumor progression. Here, the authors show Pancreatic ductal adenocarcinoma (PDAC) epithelial cells with high level of Lin28b secrete Wnt5a to upregulate Lin28b expression in cancer-associated fibroblasts, which in turn promote growth of PDAC cells via production of PCSK9.
- Zhaoqi Shu
- , Minghe Fan
- & Ying Zhao
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Article
| Open AccessA tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development
Within gastrointestinal tissues, tuft cells, a rare population of chemo-sensory epithelial cells, can promote the activation of type 2 innate lymphoid cells (ILC2s). Here the authors show that tuft cells and ILC2s are increased during gastric cancer development and that the pharmacologic inhibition of tuft cell derived IL25 or ILC2-produced IL13 reduces gastric tumor growth.
- Ryan N. O’Keefe
- , Annalisa L. E. Carli
- & Michael Buchert
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Article
| Open AccessThe liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer
The suppressive immune microenvironment in colorectal cancer (CRC) liver metastasis remains to be explored. Here, the authors find tumor-associated macrophages in the liver microenvironment induces elevated secretion of FGL1 from cancer cells and hepatocytes which promotes CRC metastasis by suppressing the infiltration of T cells.
- Jia-Jun Li
- , Jin-Hong Wang
- & Huai-Qiang Ju
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Article
| Open AccessPreservation versus resection of Denonvilliers’ fascia in total mesorectal excision for male rectal cancer: follow-up analysis of the randomized PUF-01 trial
Total mesorectal excision (TME) for rectal cancer can require partial resection of Denonvilliers’ fascia (DVF). Here the authors report the secondary outcomes of a randomized trial to evaluate the safety and effect of DVF preservation during laparoscopic TME on postoperative urogenital function and oncological safety in male patients with mid-low rectal cancer.
- Jiafeng Fang
- , Bo Wei
- & Hongbo Wei
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Article
| Open AccessLactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer
Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy.
- Lianhui Sun
- , Yuan Zhang
- & Chen Huang
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Article
| Open AccessSleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development
Chronic inflammation promotes the development and progression of colorectal cancer (CRC) while the underlying mechanism remains to be elucidated. Here, the authors perform in vivo transposon mutagenesis screening to identify that TNFα-activated senescence signaling acts as selective pressure to drive mutation of Cdkn2a and other senescence-related genes in inflammation-accelerated CRC.
- Kana Shimomura
- , Naoko Hattori
- & Haruna Takeda
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Article
| Open AccessGenomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma
Genome complexity is a distinguishing feature of advanced cancers in contrast to precancerous conditions. Here, by analysing chromosomal copy-number evolution in early cancers and precancerous lesions of the oesophagus, the authors reveal signatures of ongoing chromosomal instability and its role in promoting tumour progression.
- Chunyang Bao
- , Richard W. Tourdot
- & Cheng-Zhong Zhang
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Article
| Open AccessGenome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk
Here, the authors apply the Activity-by-Contact (ABC) model to infer enhancer-gene regulation and the effect of associated variants across multiple cancer types, integrating genetic and multi-omics data. Then, they explore the mechanisms associated with ABC regulatory variants in colorectal cancer.
- Pingting Ying
- , Can Chen
- & Xiaoping Miao
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Article
| Open AccessTHBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer
Thrombospondin-1 (THBS1) is a matricellular protein highly expressed in inflammatory processes, including cancer. Here the authors show that bone-marrow derived monocyte-like cells are the primary source of THBS1 in colorectal cancer, associated with mesenchymal characteristics, immunosuppression and a poor prognosis.
- Mayuki Omatsu
- , Yuki Nakanishi
- & Hiroshi Seno
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Article
| Open AccessTumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer
Patients with MMR-proficient, microsatellite stable (MSS) colorectal cancer (CRC) are highly resistant to immune-checkpoint inhibitors. Here the authors report that tumor intrinsic expression of the autophagy gene ATG16L1 is associated with resistance to anti-tumor immunity in preclinical CRC models and that elevated ATG16L1 expression predicts poor immunotherapy response in Kras-mutant CRC patients.
- Lucia Taraborrelli
- , Yasin Şenbabaoğlu
- & Aditya Murthy
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Article
| Open AccessKMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics
The molecular mechanisms involved in the maintenance of pancreatic cancer stem cells (PCSCs) characteristics are unclear. Here, the authors identify the histone methyltransferase KMT2A as a binding partner of the PHF5A-PHF14-HMG20A-RAI1 protein subcomplex and an epigenetic regulator of the PCSCs characteristics and show the therapeutic potential of targeting this axis in pancreatic cancer.
- Mai Abdel Mouti
- , Siwei Deng
- & Siim Pauklin
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Article
| Open AccessA super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer
The epigenetic mechanisms underlying pancreatic ductal adenocarcinoma (PDAC) are not fully elucidated. Here, the authors reveal a druggable super-enhancer-mediated RNA-binding protein cascade that supports PDAC growth through enhanced mRNA translation.
- Corina E. Antal
- , Tae Gyu Oh
- & Ronald M. Evans
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Article
| Open AccessCoordinated single-cell tumor microenvironment dynamics reinforce pancreatic cancer subtype
Multiple studies have characterised the tumour microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) using single-cell RNA-seq. Here, the authors integrate the data from such single-cell studies to provide a cohesive analysis of the PDAC TME, revealing cell types and interactions that are associated with PDAC phenotypes.
- Ki Oh
- , Yun Jae Yoo
- & Richard A. Moffitt
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Article
| Open AccessBiology-guided deep learning predicts prognosis and cancer immunotherapy response
The clinical application of data-driven deep learning models remains challenging. Here, a biology-guided deep learning approach allows the simultaneous prediction of the tumour immune and stromal microenvironment status as well as treatment outcomes from medical images in gastric cancer.
- Yuming Jiang
- , Zhicheng Zhang
- & Ruijiang Li
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Article
| Open AccessSingle cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis
The metastatic tumour microenvironment in pancreatic ductal adenocarcinoma (PDAC) remains to be explored. Here, the authors perform single cell RNA sequencing analysis for synchronously resected PDAC primary tumours and matched liver metastases and find differences in cellular composition.
- Shu Zhang
- , Wen Fang
- & Ying Lv
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Article
| Open AccessAn idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver
Cancer liver metastases can be encapsulated by a fibrotic stroma. Here the authors use digital pathology to generate spatial growth pattern maps of colorectal cancer liver metastasis and show that prognosis depends on the degree of fibrotic encapsulation.
- Carlos Fernández Moro
- , Natalie Geyer
- & Marco Gerling
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Article
| Open AccessNeoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial
Neoadjuvant chemotherapy followed by gastrectomy is considered standard of care for locally advanced gastric and gastroesophageal junction (G/GEJ) cancers. Here the authors report the results of a phase 2 trial of neoadjuvant sintilimab (anti-PD1) plus chemoradiotherapy in patients with locally advanced G/GEJ tumors.
- Jia Wei
- , Xiaofeng Lu
- & Baorui Liu
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Article
| Open AccessSpatial transcriptomics analysis of esophageal squamous precancerous lesions and their progression to esophageal cancer
Understanding the molecular changes in the transition from esophageal squamous precancerous lesions (ESPL) to esophageal squamous cell carcinoma (ESCC) remains essential. Here, the authors analyze ESPL samples using spatial transcriptomics and reveal expression changes in TAGLN2 and CRNN during progression to ESCC.
- Xuejiao Liu
- , Simin Zhao
- & Zigang Dong
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Article
| Open AccessTargeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer
KRAS mutations are associated with an immunosuppressive microenvironment in patients with colorectal cancer (CRC). Here the authors show that knockout of SLC25A22, a mitochondrial glutamate carrier, reverts KRAS-mediated immunosuppression in preclinical CRC models, by suppressing CXCL1 production and impairing MDSC recruitment.
- Qiming Zhou
- , Yao Peng
- & Chi Chun Wong
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Article
| Open AccessSchwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment
The effects of Schwann cells on the neuro-stroma niche in pancreatic ductal adenocarcinoma (PDAC) remain to be explored. Here, single-cell RNA-sequencing and spatial transcriptome analysis of PDAC tissues reveal that Schwann cells induce malignant subtypes of tumour cells and cancer associated fibroblasts.
- Meilin Xue
- , Youwei Zhu
- & Hao Chen
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Article
| Open AccessMutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin
Dynamic proteolipid nanoassemblies at the plasma membrane of colonocytes serve as Wnt signaling hubs. Here, the authors find a role for mutant APC in colorectal cancer in the dysregulation of plasma membrane sterol homeostasis.
- Alfredo Erazo-Oliveras
- , Mónica Muñoz-Vega
- & Robert S. Chapkin
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Article
| Open AccessAdipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer
Advanced pancreatic cancer is associated with tissue wasting; however, the timing of tissue loss prior to diagnosis and the potential utility of such loss for earlier pancreatic cancer detection are not well understood. Here the authors show that skeletal muscle loss can be detected on CT imaging 1–2 years before a clinical diagnosis of pancreatic cancer.
- Ana Babic
- , Michael H. Rosenthal
- & Brian M. Wolpin
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Article
| Open AccessIL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer
IL1 signalling pathway has been shown to shape cancer associated fibroblast (CAF) heterogeneity. Here the authors identify a pro-tumorigenic CAF subtype in colorectal cancer characterized by high IL1R1 expression and associated with an immunosuppressive tumor microenvironment.
- E. Koncina
- , M. Nurmik
- & E. Letellier
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Article
| Open AccessMutational signature dynamics shaping the evolution of oesophageal adenocarcinoma
It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett’s Oesophagus, as well as their prognostic associations.
- Sujath Abbas
- , Oriol Pich
- & Maria Secrier
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Article
| Open AccessLoss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons
The role of PHD finger protein 8 (PHF8) in anti-tumour immunity remains to be investigated. Here, the authors suggest PHF8 as an epigenetic checkpoint and show that targeting PHF8 induces a viral mimicry response enhancing anti-tumour immunity in colorectal cancer.
- Yanan Liu
- , Longmiao Hu
- & Xiufeng Pang
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Article
| Open AccessACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis
Diagnostic markers and therapeutic targets for gastric cancer are in urgent need. Here, the authors 2 find elevated expression of ACTL6A in gastric cancer promotes glutathione synthesis by regulating 3 GCLC expression to suppress ferroptosis.
- Ziqing Yang
- , Shaomin Zou
- & Lekun Fang
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Article
| Open AccessInterventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy
Minimally invasive irreversible electroporation shows some therapeutic promise in irresectable pancreatic cancers that are notorious for poor survival. Here authors combine this with administration of a hydrogel microsphere vaccine that augments the antigen presentation T cell response cascade that naturally initiates following ablation.
- Xiaoyu Liu
- , Yaping Zhuang
- & Zhongmin Wang
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Article
| Open AccessGenome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma
The availability of relevant animal models that can recapitulate high-risk hepatoblastoma will help to better understand its pathogenesis. Here the authors report and characterize a hepatocyte-specific, MYC-driven hepatoblastoma mouse model and show it recapitulates the human hepatoblastoma pathophysiology.
- Jie Fang
- , Shivendra Singh
- & Jun Yang
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Article
| Open AccessThe transcriptional landscape and diagnostic potential of long non-coding RNAs in esophageal squamous cell carcinoma
Esophageal squamous cell carcinoma is difficult to detect at early stages, and late detection is often linked to poor prognosis. Here, the authors develop a lncRNA signature predictive of ESCC and validate across multiple external cohorts.
- Meng Zhou
- , Siqi Bao
- & Zhihua Liu
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Article
| Open AccessOncogenic structural aberration landscape in gastric cancer genomes
Gastric cancers (GC) are driven by genomic alterations, but the underlying molecular mechanisms remain unclear. Here, the authors analyse the structural rearrangement landscape of 170 GCs using whole-genome sequencing, identify recurrent structural variant hotspots and find oncogene amplicons driven by extrachromosomal DNA.
- Mihoko Saito-Adachi
- , Natsuko Hama
- & Tatsuhiro Shibata
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Article
| Open AccessA platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma
GM-CSF-secreting whole-cell cancer vaccine (GVAX) promotes T-cell response against a range of tumor associated antigens in patients with pancreatic adenocarcinoma (PDA). Here the authors report the results of the initial three treatment arms of a platform trial of neoadjuvant and adjuvant GVAX alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable PDA.
- Thatcher Heumann
- , Carol Judkins
- & Lei Zheng
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Article
| Open AccessPacpaint: a histology-based deep learning model uncovers the extensive intratumor molecular heterogeneity of pancreatic adenocarcinoma
Rapid and effective molecular subtyping of pancreatic adenocarcinoma (PDAC) is important for prognosis and treatment. Here, the authors develop PACpAInt, a deep learning model for PDAC molecular subtyping from whole-slide histological imaging that enables the analysis of heterogeneity and prognostic predictions.
- Charlie Saillard
- , Flore Delecourt
- & Jerome Cros
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Article
| Open AccessTranscriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner
Expression of the metabolic enzyme CD73 has been associated with immunosuppression in cancer. Here the authors show that tumor cell-autonomous CD73 promotes regulatory T-cell accumulation and that CD73 targeting sensitizes pancreatic cancer to PD-1 blockade.
- Tianyu Tang
- , Xing Huang
- & Tingbo Liang
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Article
| Open AccessFinal results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer
HER2 amplification in metastatic colorectal cancer (mCRC) identifies a group of patients with poorer prognosis. Here, the authors report the results of a phase II clinical trial assessing the clinical response and safety of trastuzumab deruxtecan as a third-line treatment in patients with mCRC with different HER2 expression levels
- Takayuki Yoshino
- , Maria Di Bartolomeo
- & Maria Di Bartolomeo
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Article
| Open AccessMulti-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy
It remains critical to understand the genomic events in response to treatment of oesophageal adenocarcinoma (OAC). Here, the authors perform a multi-omics analysis of OAC patients from the DOCTOR phase II clinical trial, finding genomic features and immune clusters associated with survival.
- Marjan M. Naeini
- , Felicity Newell
- & Nicola Waddell
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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 AccessHyperphosphorylated PTEN exerts oncogenic properties
PTEN has tumor suppressive functions. Here the authors report that PTEN C-tail hyperphosphorylation promotes neoplastic growth through oncogenic activation of WNT signalling.
- Janine H. van Ree
- , Karthik B. Jeganathan
- & Jan M. van Deursen
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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 AccessAlternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes
The regulatory mechanisms of alternative promoters remain to be investigated. Here, the authors explore the sequence and epigenetics landscape of alternative promoters and how they regulate gene expression in hepatocellular carcinoma.
- Chirag Nepal
- & Jesper B. Andersen
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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 AccessPancreatic cancer is associated with medication changes prior to clinical diagnosis
Pancreatic cancer patients have previously been noted to have a change in medication history prior to diagnosis. Here, the authors utilise two large population cohorts to show associations between recent medication changes and risk of a subsequent pancreatic cancer diagnosis.
- Yin Zhang
- , Qiao-Li Wang
- & Brian M. Wolpin
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Article
| Open AccessProtein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development
NF-κB activation contributes to colitis-associated colorectal cancer (CAC). Here the authors show that NF-κB subunit, p65 stabilizes ITF2, which then suppresses NF-κB downstream genes and inhibits CAC progression.
- Mingyu Lee
- , Yi-Sook Kim
- & Hyun-Woo Shin