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Colorectal cancer is the world’s fourth deadliest cancer, with the highest incidences in developed countries. The risk of developing the disease depends on many factors, including genetics, medical conditions such as ulcerative colitis and Crohn’s disease, diet and lifestyle. The prognosis for patients is favourable if diagnosed at the earliest stage and, in this case, surgery is the treatment of choice. However, for patients who present at a later stage, marked by metastatic spread of tumour cells to the lymph nodes and other sites in the body, treatment consists of a combination of general chemotherapy and molecular targeted therapy.
On the occasion of National Colorectal Cancer Awareness Month (US) in March, the cancer team at Nature Communications has curated a collection of research articles that shed light on the molecular and genetic pathogenesis of colorectal cancer as well on new therapeutic and diagnostic options. These insights could help improve outcomes for patients affected by this disease.
Intestinal cancer stem cells (CSC) are associated with colon cancer. Here, the authors show that Wnt/beta-catenin signalling in CSC requires the epigenetic regulator Mll1 to promote stemness and tumourigenesis in murine and human colon cancer models.
Expression patterns of immune checkpoints in patients with gastric cancer remain poorly characterized. Here the authors propose an immune scoring system based on the expression of six immunosuppressive ligands to improve the prognostic accuracy in gastric cancer patients and drive the selection of candidates for adjuvant chemotherapy.
Expression and activation of Heat shock factor 1 (HSF1) in cancer associated fibroblasts have been associated with protumorigenic functions. Here the authors show that, in a model of colitis-induced colorectal cancer, HSF1 is activated in stromal fibroblasts in the early stages of inflammation, leading to extracellular matrix remodelling that sustains tumor initiation and progression.
The alternative mechanisms of innate immunity in tumorigenesis of colorectal cancers are unclear. Here, the authors report a non-canonical function of IRF3, a mediator of innate immune signalling, in the suppression of colorectal tumorigenesis and this is via the inhibition of Wnt/β-catenin pathway.
Cancer patient classification using predictive biomarkers for anti-cancer drug responses is essential for improving therapeutic outcomes. Here, the authors present a machine-learning framework to identify robust drug biomarkers by taking advantage of network-based analyses using pharmacogenomic data.
The relative enrichment of cancer stem cells after treatment results in tumour recurrence. Here, the authors show a mechanism where p53 induces WNT3, which increases the number of colorectal cancer stem cells following treatment of 5-fluorouracil.
DNA mismatch repair (MMR)-deficient cancers with microsatellite-instability are characterized by a high load of frameshift mutation-derived neoantigens. Here, by mapping the frameshift mutation landscape and predicting the immunogenicity of the resulting peptides, the authors show evidence of immunoediting in MMR-deficient colorectal and endometrial cancers.
The oncogene KRAS is frequently mutated in cancer, including colorectal cancer. Here, using a cell-surface proteomics approach, KRAS-mutated colorectal cancer cells are shown to express high levels of the copper transporter ATP7A, which has an essential roles in cancer cell survival and proliferation.
Patients whose disease is diagnosed in its early stages have better outcomes. In this study, the authors develop a non invasive blood test based on circulating tumor DNA methylation that can potentially detect cancer occurrence even in asymptomatic patients.
Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.
Spatial information in the tumour microenvironment may be exploited to optimise diagnosis, prognosis and therapy. Here, the authors develop a spatial analytics computational and systems pathology platform (SpAn) based on highly multiplexed antibody imaging on colorectal cancer samples to infer emergent network biology and predict 5-year risk of recurrence.
Polyamine metabolism is frequently dysregulated in cancers. Here, the authors show that a polyamine biosynthetic enzyme, spermine synthase, is overexpressed in colorectal cancers and cooperates with MYC to prevent cancer cell apoptosis by repression of proapoptotic protein, Bim.
Phosphodiesterase-5 (PDE5) inhibitors have been suggested to have an anti-tumor effect and block surgery-induced immunosuppression. Here, the authors show that postdiagnostic use of PDE5 inhibitors is associated with a decreased risk of colorectal cancerspecific mortality as well as a decreased risk of metastasis.
Colonoscopy is the most commonly used tool to screen for colorectal cancer (CRC). Here, the authors develop a deep learning model to perform optical diagnosis of CRC by training on a large data set of white-light colonoscopy images and achieve endoscopist-level performance on three independent datasets.
Poly-functional helper T cells can have a stronger effect than mono-functional T cells, but whether the response is qualitatively different is not clear. Here the authors show that a population of IL-17+IL-22+, but not single IL-22+, CD4+ T cells are induced by TGF-β, enriched in patients with colorectal cancer (CRC) and drive CRC progression in mice.
Fasting diets are emerging as an approach to delay tumor progression and improve cancer therapies. Here, the authors show that the combination of fasting-mimicking diet with vitamin C decreases tumor development and increases chemotherapy efficacy in KRAS-mutant cancer.
The role of long non-coding RNAs (lncRNAs) in metastatic colorectal cancer (mCRC) and treatment resistance is unclear. Here, the authors use transcriptome sequencing of matched normal, primary, and metastatic CRC tissues to discover and validate that lncRNA RAMS11 promotes metastasis and resistance to topoisomerase inhibitors in mCRC.
Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC). Here, the authors analysed the primary tumours, lymph node metastasis and liver metastasis of ten CRC patients and reveal co-existence of diverse modes of metastasis in the same patient.
Molecular analysis of archival formalin-fixed clinical tissues can be difficult. Here, researchers have developed MethCORR, an approach that infers gene expression from DNA methylation data and use the approach for molecular characterization and prognostication of colorectal cancer using archival samples.
The molecular mechanisms underpinning how fasting inhibits tumourigenesis are not completely elucidated. Here, the authors show that fasting upregulates the cholesterogenic gene FDFT1 which leads to decreased AKT/mTOR/HIF1a signalling and glycolysis reduction in colorectal cancer.
It is unclear how microbial-induced inflammation promotes neoplastic transformation in colitis-associated cancer (CAC). Here, the authors use models of CAC to show that inflammation induces 8-oxoguanine lesions in DNA, and that antioxidants can reduce these DNA lesions as well as CAC.
Allelic losses occurring in cancer cells have been suggested as potential targets for therapy. Here, the authors show how recurring loss of heterozygosity of a drug metabolic gene in colorectal cancers can be exploited using a low molecular weight compound.
Invasion is a critical step in tumor development. Here, in colorectal cancer, the authors show that multiclonal invasion of the muscularis mucosae is pervasive, suggesting that invasive capacity is not a significant bottleneck in the evolution of the disease.
The interplay between driver mutations and aneuploidy during tumorigenesis is largely unexplored. Here, the authors show two types of associations, leading to different therapeutic vulnerabilities and prognoses.
STEAP4 promotes the uptake of copper, and copper is known to be enhanced in cancer tissues. Here, the authors show that STEAP4 is induced by IL17, which is increased in inflamed tissues, consequently the increased copper levels activate NFκB signalling and suppression of apoptosis.
Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.
BCL9 is an activator of oncogenic Wnt/β-catenin. Here, the authors show a β-catenin independent function of BCL9 in a subtype of colorectal cancers, where it interacts with paraspeckle proteins to enhance the mRNA stability of calcium signalling and neural associated genes to promote communication with tumour cells and its microenvironment.
Dysfunctional autophagy induces inflammation that contributes to tumorigenesis. Here, the authors show that loss of BRG1 impairs autophagy and enhances reactive oxygen species production to disrupt intestinal barrier integrity, leading to spontaneous colitis and subsequent colorectal cancer development.
Radiofrequency ablation is used to treat metastatic colorectal cancer. In this study, the authors show that incomplete ablation of tumours results in metastases and show in mouse models that the chemokine CCL2 recruits myeloid cells to the partially ablated tumours, which can block T cell function.
CD36 is a membrane glycoprotein that has been shown to have tumour promoting or suppressor function depending on tumour type. Here, the authors address CD36 function in colorectal cancer and show it acts as a tumour suppressor by inhibiting B-catenin/myc signalling, resulting in downregulation of glycolysis.
Activating oncogenic mutations in KRAS and NRAS are common in colorectal cancer, which is a heterogenous disease. Here, the authors show that the RAS mutation spectrum is markedly different between colon and rectal cancer, and also different based on age of diagnosis and microsatellite instability.
The development of brain metastases is a lethal yet poorly understood event in the evolution of many cancers. Here, the authors perform whole-genome and whole-exome sequencing on matched normal, primary and metastatic tissue samples to explore the genomic features of brain metastases in colorectal cancer.
Activated hepatic stellate cells are associated with fibrosis and liver metastases. Here, the authors identify an endogenous role of relaxin in regulating the activation of hepatic stellate cells and report nanoparticle-mediated relaxin gene therapy to mitigate fibrosis and liver metastasis.
In tumours aberrant epigenetic modifications can alter the transcriptional state. Here, the authors identify a common tumour-specific shift to transcriptional repression associated with DNA methylation and chromatin dysregulation at the transcription start site.
In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.
The presence of bivalent epigenetic active and repressive histone marks control lineage-specific differentiation in embryonic stem cells. Here, the authors reveal that bivalent marks repress the differentiation gene IHH in colorectal cancer-initiating cells, and can be targeted by EZH2 inhibition
Somatic alterations in the exonuclease domain of DNA polymerase ɛ have been linked to the development of highly mutated cancers. Here, the authors report that a major consequence of the most common cancer-associated Polɛ variant is a dramatically increased DNA polymerase activity.
Wilms tumor gene on the X chromosome (WTX) is commonly downregulated in human cancers. Here the authors show that in colorectal cancer (CRC) WTX expression is downregulated via miR20a and miR160a and its loss promotes tumor development and liver metastasis by disrupting the interaction between RhoGDIα and CDC42 leading to the activation of the CDC42 downstream cascades.
Increased copy number alterations, indicative of chromosomal instability, is associated with poor cancer outcome. Here, metastatic colorectal cancer patients displaying intermediate-high CIN associate with improved outcome following chemotherapy and bevacizumab treatment, suggesting CIN as a predictive biomarker.
In this study the authors examine the allelic imbalance (AI) landscape of colorectal cancer, reporting loss of TP53 as a driver of AI. They use CRISPR-Cas9 screens to identify 79 genes (within AI regions) regulating cell growth and identify a network of transcription factors that may contribute to colorectal tumorigenesis.
The c-MYC oncoprotein has many targets whose actions are not fully understood including TFAP4/AP4. Here, the authors show in a mouse model of inherited colorectal cancer that deletion of AP4 decreased the frequency of c-MYC-driven intestinal adenomas, and reveal Ap4 as a mediator of adenoma initiation and regulator of colonic and intestinal stem cell and Paneth cell homeostasis.
Aberrant and persistent activation of the transcription factor STAT3 has been found in various types of cancers. Here the authors identify TRIM27 as a positive regulator of IL-6-induced STAT3 activation through the formation of JAK1-STAT3 complex, thus impacting inflammation-induced colon cancer development.
Advanced colorectal cancers are characterised by intra-tumour heterogeneity dictated by neutral evolution. Here the authors analyse early colorectal tumours by whole-exome sequencing and find that Darwinian evolution determines the fate of early lesions in colorectal adenoma and carcinoma in situ.
The emergence of sub-clones that are resistant to targeted agents is a major therapeutic obstacle in oncology. Here, using colorectal cancer as a model system, the authors show that interfering with ancestral oncogenic events present in all subclones-like APC-WNT pathway alterations—can restrain the emergence of drug-resistant populations.
Microsatellite-stable (MSS) colorectal cancer (CRC) has shown poor response to checkpoint blockade immunotherapy. Here, the authors show that the combination of oxaliplatin with anti-PDL1 mAb is specifically efficient in the treatment of MSS CRC.
The ERK signalling pathway regulates homeostasis of the intestinal epithelium. Here the authors identify two modes of ERK activity generated independently from EGFR and ErbB2 receptor and whose balance in cancer is shifted by Wnt pathway activation, resulting in enhanced sensitivity to EGFR inhibitors.
Tumour associated macrophages (TAMs) polarize into either pro-tumor or anti-tumor phenotypes. Here the authors show that the homeobox protein VentX is downregulated in clinical samples of colorectal cancer and regulates TAMs plasticity with its forced re-expression converting TAMs into an anti-tumor phenotype.
Wnt ligands are essential for intestinal homoeostasis and stem cell maintenance. Here, the authors show that reduction in Wnt secretion reduces the number of intestinal stem cells; this results in rapid fixation of mutated stem cells and accelerated adenoma formation due to lack of cell competition.