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| Open AccessTransposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer
It has been suggested that transposable elements (TE) play a role in tumourigenesis, but the associated mechanisms remain unclear. Here, the authors show, using colorectal cancer data and Bayesian Networks, that TEs can mediate the effect of expression quantitative trait loci and contribute to the regulation of cancer-related genes.
- Nikolaos M. R. Lykoskoufis
- , Evarist Planet
- & Emmanouil T. Dermitzakis
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Article
| Open AccessRobustly federated learning model for identifying high-risk patients with postoperative gastric cancer recurrence
Medical data faces isolation and cross-center performance issues. Here, the authors propose a robust federated learning model to identify high-risk postoperative gastric cancer recurrence, achieving promising results across data from four independent medical institutions.
- Bao Feng
- , Jiangfeng Shi
- & Wansheng Long
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Article
| Open AccessEngineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
There is an unmet medical need for the detection and treatment of early adenomas to prevent their progression to malignant disease. Here the authors show that orally administered E. coli Nissle 1917 can selectively colonize adenomas in mouse models and in patients as a detection tool, as well as deliver immunotherapeutics for colorectal neoplasia treatment.
- Candice R. Gurbatri
- , Georgette A. Radford
- & Tal Danino
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Article
| Open AccessMutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death
Oncogenic KRAS mutations can dictate the formation of an immune-suppressive tumor microenvironment. Here the authors report that, in KRAS mutant colorectal cancer, the upregulation of circATXN7 in tumor-specific cytotoxic T lymphocytes is associated with increased sensitivity to activation-induced cell death and resistance to immunotherapy.”
- Chi Zhou
- , Wenxin Li
- & Huashan Liu
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Article
| Open AccessA transcriptome based molecular classification scheme for cholangiocarcinoma and subtype-derived prognostic biomarker
Cholangiocarcinoma can arise anywhere within the biliary tree and is classified by anatomical locations. Here, the authors utilised RNAseq from 438 CCA patients and propose a molecular classification system independent of location.
- Zhongqi Fan
- , Xinchen Zou
- & Guoyue Lv
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Article
| Open AccessTET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer
Activation of the cGAS-STING pathway has been associated with the promotion of anti-tumor immunity. Here the authors show that TET2 upregulates tumor cGAS to activate STING in endothelial cells, inducing tumor vascular normalization and enhancing efficacy of anti-PD-L1 alone or combined with IL-2 in liver cancer preclinical models.
- Hongwei Lv
- , Qianni Zong
- & Wen Yang
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Article
| Open AccessAvapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
Avapritinib, a potent inhibitor, offers hope for D842V-mutant GIST patients with high response rates; however, resistance and side effects remain challenges. Here, crystal structures shed light on this and reveal a Gα-pocket for drug development.
- A. Teuber
- , T. Schulz
- & D. Rauh
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Article
| Open AccessNeoadjuvant camrelizumab and apatinib combined with chemotherapy versus chemotherapy alone for locally advanced gastric cancer: a multicenter randomized phase 2 trial
Neoadjuvant treatment represents a therapeutic option for locally advanced gastric cancer (LAGC). Here the authors report the results of a randomized phase 2 trial of camrelizumab (anti-PD1) and apatinib (anti-VEGFR2) combined with nab-paclitaxel plus S-1 versus chemotherapy alone as neoadjuvant treatment for LAGC.
- Jian-Xian Lin
- , Yi-Hui Tang
- & Chang-Ming Huang
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Article
| Open AccessKRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo
The function of wild-type KRAS in KRAS mutant cancers remains to be explored. Here, the authors show that deletion of the tumour-suppressive wild-type Kras in a KRASG12D driven colon cancer model exacerbates tumour initiation in a MAPK dependent manner, while acting to suppress metastasis through impaired immune suppression.
- Arafath K. Najumudeen
- , Sigrid K. Fey
- & Owen J. Sansom
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Article
| Open AccessRBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing
The role of alternative splicing in pancreatic cancer (PDAC) development remains to be explored. Here, RBFOX2 is shown to regulate exon splicing events in transcripts encoding proteins involved in cytoskeletal remodelling programs and its downregulation promotes PDAC progression and liver metastasis.
- Michelle Maurin
- , Mohammadreza Ranjouri
- & Karen M. Mann
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Article
| Open AccessProteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of hepatocellular carcinoma
Hepatocellular carcinoma is often diagnosed at a late stage which limits treatment efficacy. Here, the authors utilise proteomics to identify serum proteomic biomarkers for early diagnosis, and validate using a prospective validation cohort.
- Xiaohua Xing
- , Linsheng Cai
- & Xiaolong Liu
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Article
| Open AccessDeep learning-based phenotyping reclassifies combined hepatocellular-cholangiocarcinoma
Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.
- Julien Calderaro
- , Narmin Ghaffari Laleh
- & Jakob Nikolas Kather
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Article
| Open AccessEnhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis
The underlying mechanisms driving colorectal cancer (CRC) through the serrated route are largely unknown. Here, the authors show that reduced aPKC levels increase cholesterol biosynthesis to promote aggressiveness in serrated tumours and targeting this pathway reduces tumourigenesis in preclinical models of serrated CRC.
- Yu Muta
- , Juan F. Linares
- & Jorge Moscat
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Article
| Open AccessLncRNA MIR200CHG inhibits EMT in gastric cancer by stabilizing miR-200c from target-directed miRNA degradation
The roles of long non-coding RNAs (lncRNAs) in different subtypes of gastric cancer (GC) remain to be characterized. Here, the authors identify lncRNA MIR200CHG as a master regulator of Microsatellite stable (MSS)/epithelial-mesenchymal transition (EMT) GC subtype, which inhibits EMT and metastasis by stabilizing miR-200c.
- Yixiao Zhu
- , Chengmei Huang
- & Xin Wang
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Article
| Open AccessMapping and modeling human colorectal carcinoma interactions with the tumor microenvironment
Tumour-microenvironment interactions, pivotal in cancer progression, are challenging to replicate in vitro. Here, the authors use single-cell RNA-seq to analyse these interactions in colorectal cancer within organoid models, and aim to emulate and understand these crucial interactions by introducing specific microenvironmental components.
- Ning Li
- , Qin Zhu
- & Christopher J. Lengner
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Article
| Open AccessSPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma
In liver cancer, the presence of tumour-initiating cell subsets are associated with poorer prognosis and chemotherapy resistance in liver cancer. Here, the authors show that upon treatment with 5-FU or cisplatin, this subset releases SPINK1 which binds EGFR, activating the ERK-CDK4/6-E2F2 signaling cascade and resulting in chemoresistance.
- Ki-Fong Man
- , Lei Zhou
- & Stephanie Ma
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Article
| Open AccessContribution of pks+ E. coli mutations to colorectal carcinogenesis
Common driver mutations in colorectal cancer (CRC) are not always consistent with frequent mutational signatures. Here, the authors analyse spatially annotated colon crypts in CRC patients and find mutational signatures of pks+ E. coli that are consistent with driver mutations, suggesting a potential role of pks+ E. coli in carcinogenesis.
- Bingjie Chen
- , Daniele Ramazzotti
- & Andrea Sottoriva
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Article
| Open AccessPD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma
Although atezolizumab and bevacizumab have changed the treatment landscape of advanced hepatocellular carcinoma, the factors that determine responsiveness to treatment remain unclear. Using single-cell RNA sequencing, the authors identify specific macrophage and T cell subsets that are enriched in patients with durable responses.
- Sarah Cappuyns
- , Gino Philips
- & Jeroen Dekervel
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Article
| 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