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| 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 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 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 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 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 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 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 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 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 AccessLongitudinal plasma proteome profiling reveals the diversity of biomarkers for diagnosis and cetuximab therapy response of colorectal cancer
Resistance to cetuximab is a common feature of colorectal cancer progression. Here, the authors utilize longitudinal proteomic profiling of 147 colorectal cancer patients and find potential biomarkers which can predict treatment response.
- Yan Li
- , Bing Wang
- & Chen Ding
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Article
| 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 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 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 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 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 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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| 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 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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| 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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| 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 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 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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| 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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| 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 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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| 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 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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| 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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| 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 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
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| 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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| Open AccessBlocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression
The effect of β-glucans and their receptor Dectin-1 in tumor development remains controversial. Here the authors show that Dectin-1 signaling promotes the development of colorectal cancer (CRC) by inducing prostaglandin E2 production in myeloid-derived suppressor cells and by suppressing IL-22BP expression, suggesting dectin-1 blockade as a potential therapeutic target for CRC.
- Ce Tang
- , Haiyang Sun
- & Yoichiro Iwakura
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Article
| Open AccessBile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer
Non-enterotoxigenic Bacteroides fragilis (NTBF) is abundant in colorectal cancer (CRC) patients and in a high-fat diet (HFD)-induced CRC model. Here the authors show that bile salt hydrolase-expressing NTBF is enriched in CRC patients with overweight and promotes tumor growth in an HFD-induced CRC mouse model.
- Lulu Sun
- , Yi Zhang
- & Frank J. Gonzalez
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Article
| Open AccessMapping lesion-specific response and progression dynamics and inter-organ variability in metastatic colorectal cancer
Understanding the heterogeneity of growth, response to therapy and progression dynamics in metastatic colorectal cancer (mCRC) remains critical. Here, the authors analyse lesion-specific response heterogeneity in 4,308 mCRC patients and find that organ-level progression sequence is associated with long-term survival.
- Jiawei Zhou
- , Amber Cipriani
- & Yanguang Cao
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Article
| Open AccessSerum metabolic traits reveal therapeutic toxicities and responses of neoadjuvant chemoradiotherapy in patients with rectal cancer
Neoadjuvant chemoradiotherapy is the standard treatment for patients with locally advanced rectal cancer, however, response can be limited by development of toxicities. Here, the authors conducted metabolomics on patients with locally advanced rectal cancer enrolled in a phase III clinical study and identify serum metabolites associated with treatment response.
- Hongmiao Wang
- , Huixun Jia
- & Zheng-Jiang Zhu
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Article
| Open AccessEpithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features
It remains critical to identify colorectal cancers (CRC) that will disseminate as early as possible. Here, the authors identify CRC tumours that are aggressive and prone to early dissemination, characterised by epithelial TGFβ and growth-factor signalling - which could be targeted with MEK/EGFR inhibitors.
- Dustin J. Flanagan
- , Raheleh Amirkhah
- & Owen J. Sansom
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Article
| Open AccessInflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer
Inflammatory conditions often affect colorectal cancer patients, and their effect on their ongoing treatment is a pressing medical question. Here authors show that inflammation interferes with local anti-tumour immune response and inhibits response to immune checkpoint blockade therapy via immunosuppressive neutrophil leukocytes.
- Qiaoqi Sui
- , Xi Zhang
- & Pei-Rong Ding
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Article
| Open AccessMutant RIG-I enhances cancer-related inflammation through activation of circRIG-I signaling
By recognizing double-stranded RNA, RIG-I is implicated in anti-viral immune responses, but also in cancer development and intestinal inflammation. Here the authors identify frameshift germline mutations of RIG-I, resulting in the generation of a circular RNA associated with increased susceptibility to colitis-associated colon cancer.
- Jia Song
- , Wei Zhao
- & Dan Lu
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Article
| Open AccessGZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in non-metastatic colorectal tumors and predict poor clinical outcome
The tumor immune microenvironment is an important prognostic determinant in colorectal cancer (CRC). Here the authors show that tumor infiltrating neutrophils expressing high levels of CD15 interact with CD8+ T effector memory skewing them to produce GZMK, associated with tumor progression in CRC patients.
- Silvia Tiberti
- , Carlotta Catozzi
- & Teresa Manzo
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Article
| Open AccessSirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability
Sirtuin 5 (SIRT5) has been associated to colorectal cancer and metabolic regulation. Here, the authors show that SIRT5 silencing reduces nucleotide availability leading to DNA damage and tumor suppression in colorectal cancer models.
- Hao-Lian Wang
- , Yan Chen
- & Jing-Yuan Fang
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Article
| Open AccessCommon anti-cancer therapies induce somatic mutations in stem cells of healthy tissue
Specific anti-cancer therapies are highly mutagenic to cancer cells but the mutational impact on healthy tissues remains elusive. Here, the authors use organoids and whole-genome sequencing to characterise somatic mutations in healthy colon and liver adult stem cells after chemo- or radiotherapy.
- Ewart Kuijk
- , Onno Kranenburg
- & Arne Van Hoeck
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Article
| Open AccessUSP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer
IDO1-mediated tryptophan metabolism plays an important role in creating an immunosuppressive tumour microenvironment. Here, the authors show that deubiquitinase USP14 regulates immune suppression by inducing IDO1 stabilization and suggest USP14 as a potential therapeutic target to improve immunotherapy in colorectal cancer.
- Dongni Shi
- , Xianqiu Wu
- & Wenting Liao
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Article
| Open AccessARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer
ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated colorectal cancer tumors, however, its relationship with treatment response remains to be explored. Here, the authors suggest that ARID1A mutations may confer intrinsic and acquired resistance to cetuximab treatment.
- Radia M. Johnson
- , Xueping Qu
- & Carlos Bais
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Article
| Open AccessCK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis
Hippo signalling is often deregulated in cancers. Here the authors show that CK2 enhances the cooperation of HHEX with YAP-TEAD complex to promote colorectal tumorigenesis.
- Yuegui Guo
- , Zhehui Zhu
- & Chen-Ying Liu
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Article
| Open AccessGenome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA
Detection of mutational signatures in cell-free DNA (cfDNA) is challenging due to low sequence coverage and low mutant allele fractions. Here, the authors identify mutational signatures in plasma whole genome sequencing of cancer patients and use machine learning to distinguish them from healthy individuals.
- Jonathan C. M. Wan
- , Dennis Stephens
- & Luis A. Diaz Jr.
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Article
| Open AccessMolecular characterization of colorectal cancer related peritoneal metastatic disease
Colorectal cancer can lead to the development of peritoneal metastases, which are associated with worse disease outcome. Here, the authors characterize peritoneal metastases from 52 patients using RNA-seq and mutational sequencing and show a distinct molecular subtype.
- Kristiaan J. Lenos
- , Sander Bach
- & Louis Vermeulen
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Article
| Open AccessAcetyl-CoA-Carboxylase 1-mediated de novo fatty acid synthesis sustains Lgr5+ intestinal stem cell function
Here the authors report that inhibition of de novo fatty acid synthesis by deleting the enzyme Acetyl-CoA-Carboxylase 1 in the intestinal epithelium results in the loss of crypt structures and a specific decline in Lgr5+ intestinal epithelial stem cells.
- Shuting Li
- , Chia-Wen Lu
- & Matthias Lochner
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Article
| Open AccessThe cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
Looking for metabolic-associated vulnerabilities is a promising approach for therapeutic intervention in KRAS-mutant colorectal cancer. Here, the authors show that the cholesterol-uptake regulator PCSK9 drives tumourigenesis and is a therapeutic target in KRASmutant colorectal cancer.
- Chi Chun Wong
- , Jian-Lin Wu
- & Jun Yu