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Including data from 1,047 patients across 19 inflammatory diseases, a new atlas presents a comprehensive model of inflammation in circulating immune cells.

In colorectal cancer, therapeutic resistance is driven by MAPK-dependent epithelial cell plasticity.

Single-cell RNA sequencing of colorectal tumors highlights associations between lineage-related gene expression signatures and specific stromal and immune cell populations.

Controlling for confounders calls into question the robustness of some associations of microbiota with colorectal cancer stages.

A single-cell transcriptomic analysis of 63 patients with colorectal cancer classifies tumor cells into two epithelial subtypes. An improved tumor classification based on epithelial subtype, microsatellite stability and fibrosis reveals differences in pathway activation and metastasis.

This Review discusses recent evidence that indicates that different genetic alterations might be related to distinct sensitivity to targeted therapies. It examines prototypical examples and asks what is the role of cancer mutations as predictors of sensitivity and resistance to targeted therapies? Further, what are the implications for the 'personalized' treatment of cancer patients?

The chromatin-remodelling enzyme ATRX and the transcription factor HNF4A are identified as pivotal regulators of colonic epithelial identity, with roles in metastasis in colorectal cancer.

The current drug development procedures are far from optimal, owing to the continuous development of the health systems and the clinical research landscape. The European Organisation for Research and Treatment of Cancer proposes in this Perspective the use of collaborative molecular screening platforms (CMSPs) as a new approach for drug development. These CMSPs have the advantage of optimizing expertise of several partners and combining efforts alongside with cost-sharing models for efficient patient selection.

Predictive biomarkers are invaluable for successful and cost-effective treatment of cancer, however, biomarker discovery is difficult and requires multiple independent studies to identify suitable predictors of efficacy. Clinical trials performed in the USA, Europe or Asia can offer unique opportunities for biomarker discovery and validation. In this Perspectives, the authors describe the current fragmented approach to biomarker discovery and validation, highlighting how collaborative engagement of the academic, regulatory and pharmaceutical communities can help address these issues.

An international consortium of colorectal cancer researchers undertakes a large-scale data sharing project to achieve a consensus molecular classification of colorectal cancers.

Cetuximab and panitumumab have been approved for the treatment of metastatic colorectal cancer when used alone or in combination with irinotecan. Although EGFR is expressed in most metastatic colorectal tumors, only a subset of patients derive clinical benefit from treatment with EGFR inhibitors. The experimental and clinical evidence supporting the use ofKRAStesting for selecting patients for treatment with anti-EGFR monoclonal antibodies is discussed.

Few studies have suggested that enteric glial cells (EGCs) promote colorectal cancer growth. Here the authors show that EGC-derived IL-6 promotes the expansion of tumorigenic SPP1⁺ tumor-associated macrophages, associated with worse disease outcome.

The oncogenic potential of pks⁺ Escherichia coli depends critically on bacterial adhesion to host epithelial cells mediated by the type 1 pilus adhesin FimH and the F9 pilus adhesin FmlH.

Deconvolution of cfDNA fragmentation benefits from cell type-specific reference data. Here, the authors create a disease agnostic cfDNA cell type of origin analysis and show it can successfully predict cell types of origin from plasma samples.

Analysis of colorectal cancer bulk gene expression data at the pathway level identifies a poor-prognosis subtype associated with cell differentiation. The subtypes are reproducible in single-cell data and offer biological insights beyond existing stratification strategies.

Intratumoral heterogeneity has been documented in multiple cancer types, and can be linked to treatment resistance. Here, the authors analyse multiregional samples from colorectal cancers and show gene expression subtypes which are less vulnerable to heterogeneity and may partly contribute to differential patient survival.

Right-sided colorectal cancer (rCRC) has a different mutational spectrum to the left-sided counterpart. Here the authors develop a mouse model of rCRC that recapitulates human BRAF-mutant rCRC and show that loss of TGFβ-receptor signalling and inflammation induce the development of colonic tumours with a foetal-like phenotype.

A poor prognosis gene programme in patients with colorectal cancer is expressed by a unique tumour cell population that we name high-relapse cells (HRCs), and ablation of cells expressing the HRC marker EMP1 or neoadjuvant immunotherapy prevented metastatic recurrence in mice.

Mazzone and colleagues identify the bicarbonate transporter SLC4A4 as highly abundant in epithelial duct cells in pancreatic cancer and show that its inhibition mitigates acidosis in the tumor, thereby alleviating immune suppression and overcoming immunotherapy resistance.

Batlle and colleagues report that after chemotherapy, Mex3a⁺ colorectal cancer cells represent drug-tolerant persister cells that lead to recurrence by downregulating the WNT–Lgr5⁺ stem cell program and adopting a transient regenerative state.

Insights into tumour biology require biospecimens from the primary tumour and those that reflect the patient's disease in specific contexts. Tumour samples must be representative, viable, and adequate both in quantity and quality for subsequent molecular applications. This Review article outlines the existing procedures for sample procurement and processing of next-generation biospecimens, and highlights the issues involved in this endeavour.

Van Loo and colleagues report that loss of the Zeb2 regulator of epithelial-to-mesenchymal transition from the intestinal epithelium leads to inflammation, increased intestinal permeability and colorectal cancer development, which is enhanced by the resident intestinal microbiome.

Locally advanced colorectal cancers (CRCs) with DNA mismatch repair deficiency have sensitivity to immune-checkpoint inhibitors, and evidence suggests that this is also the case for a proportion of proficient DNA mismatch repair CRCs. The authors of this Review describe the emerging clinical evidence supporting the use of neoadjuvant immune-checkpoint inhibitors in patients with CRC and discuss how clinical research (including on biomarkers) can be used to improve clinical outcomes in this setting.

The availability of targeted anticancer drugs and the relative affordability of genomic analyses has led to a growing expectation among patients with cancer that they can receive personalized treatment based on the genomic signature of their tumour. Here, we discuss some of the challenges and steps needed to bring such approaches into routine practice.

In this Review, Dienstmannet al. analyse the complex nature of colorectal cancer and the different subtypes in which this disease can be classified, advocating for a 'multi-molecular' perspective for the development of therapies to treat it.