Collection |

Colorectal Cancer Awareness Month

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.

Featured articles

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

More featured articles

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications