Explore the vast range of titles available.

Organ development and homeostasis involve dynamic interactions between individual cells that collectively regulate tissue architecture and function. To ensure the highest tissue fidelity, equally fit cell populations are continuously renewed by stochastic replacement events, while cells perceived as less fit are actively removed by their fitter counterparts. This renewal is mediated by surveillance mechanisms that are collectively known as cell competition. Recent studies have revealed that cell competition has roles in most, if not all, developing and adult tissues. They have also established that cell competition functions both as a tumour-suppressive mechanism and as a tumour-promoting mechanism, thereby critically influencing cancer initiation and development. This Review discusses the latest insights into the mechanisms of cell competition and its different roles during embryonic development, homeostasis and cancer.Cell competition results in stochastic cell turnover or elimination of less fit cells from a tissue. Although cell competition generally supports tissue development and homeostasis, it can also promote malignant growth and is subverted during ageing. Addressing how cell fitness is determined and sensed is being actively pursued.

The identification of intestinal stem cells as well as their malignant counterparts, colon cancer stem cells, has undergone rapid development in recent years. Under physiological conditions, intestinal homeostasis is a carefully balanced and efficient interplay between stem cells, their progeny and the microenvironment. These interactions regulate the astonishingly rapid renewal of the intestinal epithelial layer, which consequently puts us at serious risk of developing cancer. Here we highlight the microenvironment-derived signals that regulate stem-cell fate and epithelial differentiation. As our understanding of normal intestinal crypt homeostasis grows, these developments may point towards new insights into the origin of cancer and the maintenance and regulation of cancer stem cells.

Key Points Molecular alterations fostering the progression of colorectal cancers are acquired early in the carcinogenesis process, and there is inter-connectivity among genomic drivers (gene mutations and chromosomal instability), transcriptomic subtypes (microsatellite instability immune, canonical, metabolic or mesenchymal) and immune signatures (highly immunogenic, poorly immunogenic or inflamed and immune tolerant). Primary and metastatic samples display major similarities at the genomic level: novel gene alterations are usually related to chemotherapy or targeted therapy pressure. More studies on inter-metastatic spatial heterogeneity, molecular shifts at the transcriptomic level and changes in microenvironment markers are needed. Until recently, the evolution of biomarkers for targeted therapies in colorectal cancer has been restrictive, with the identification of multiple negative predictive factors determining the response to epidermal growth factor receptor (EGFR) monoclonal antibodies. At progression to these agents, there is convergent reactivation of MAPK pathway Emerging positive predictive markers for targeted therapies include infrequent genomic events, such as BRAF V600E mutations, ERBB2 amplifications, anaplastic lymphoma kinase ( ALK ) and neurotrophic receptor tyrosine kinase ( NTRK ) fusions and alterations in upstream nodes of the WNT pathway, such as ring finger protein 43 ( RNF43 ), zinc and ring finger 3 ( ZNRF3 ) and R-spondin ( RSPO ) genes. For immune checkpoint inhibitors, promising biomarkers include microsatellite instability and DNA polymerase-ε ( POLE ) mutations Biomarker–drug co-development has evolved to accommodate a 'multi-molecular, multi-drug' perspective of precision medicine. Novel contexts of vulnerability are likely to be identified, leading to drug-repurposing strategies and combination therapies to halt tumour evolution and tackle minimal residual disease. In this Review, Dienstmann et 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. Critical driver genomic events in colorectal cancer have been shown to affect the response to targeted agents that were initially developed under the 'one gene, one drug' paradigm of precision medicine. Our current knowledge of the complexity of the cancer genome, clonal evolution patterns under treatment pressure and pharmacodynamic effects of target inhibition support the transition from a one gene, one drug approach to a 'multi-gene, multi-drug' model when making therapeutic decisions. Better characterization of the transcriptomic subtypes of colorectal cancer, encompassing tumour, stromal and immune components, has revealed convergent pathway dependencies that mandate a 'multi-molecular' perspective for the development of therapies to treat this disease.

Key Points Intestinal stem cells (ISCs) are not static entities but are instead involved in many dynamical processes. ISCs are equipotent and continuously replace each other in neutral events. The ISC phenotype is the sum of all markers and features that are commonly associated with stem cells in the intestine. Therefore, the ISC phenotype is continuously changing as new markers and features are being identified. ISC activity is the ability of cells to initiate clonal long-term, multipotent lineages and is typically assessed by lineage tracing experiments. ISC potential refers to the display of ISC activity solely in a specific context but not during homeostasis; for example, during regeneration after tissue injury. Examples of intestinal cells with ISC potential are label-retaining Paneth cell precursors and Delta-like 1-positive (DLL1 + ) secretory precursors. The functional ISC compartment is the number of cells with ISC activity corrected for their relative contribution to the total output of the stem cell compartment. Mutations that are commonly found in colorectal cancer (CRC), such as adenomatous polyposis coli ( APC ) inactivation and KRAS activation, act on ISC dynamics and give a competitive advantage to the cell in which they occur. The benefit of mutated ISCs over wild-type ISCs is not absolute, and mutated ISCs are frequently outcompeted by wild-type ISCs. CRCs contain cells with stem cell-like activity; however, the frequency of these cells remains unknown, as does the importance of these cells for the biology of CRCs. Differentiated cancer cells and cancer stem cells are in constant flux, which is influenced by signals that emanate from the tumour stroma. This Review discusses recent studies that offer quantitative insights into the dynamics of intestinal stem cell behaviour that govern homeostasis. These studies provide the necessary baseline parameters such that we can begin to understand stem cell behaviour during colorectal cancer development. Intestinal stem cells (ISCs) and colorectal cancer (CRC) biology are tightly linked in many aspects. It is generally thought that ISCs are the cells of origin for a large proportion of CRCs and crucial ISC-associated signalling pathways are often affected in CRCs. Moreover, CRCs are thought to retain a cellular hierarchy that is reminiscent of the intestinal epithelium. Recent studies offer quantitative insights into the dynamics of ISC behaviour that govern homeostasis and thereby provide the necessary baseline parameters to begin to apply these analyses during the various stages of tumour development.

Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer.

Peritoneal metastases are a common form of tumor cell dissemination in gastrointestinal malignancies. Peritoneal metastatic disease (PMD) is associated with severe morbidity and resistance to currently employed therapies. Given the distinct route of dissemination compared with distant organ metastases, and the unique microenvironment of the peritoneal cavity, specific tumor cell characteristics are needed for the development of PMD. In this review, we provide an overview of the known histopathological, genomic, and transcriptomic features of PMD. We find that cancers representing the mesenchymal subtype are strongly associated with PMD in various malignancies. Furthermore, we discuss the peritoneal niche in which the metastatic cancer cells reside, including the critical role of the peritoneal immune system. Altogether, we show that PMD should be regarded as a distinct disease entity, that requires tailored treatment strategies. Graphical Abstract In this review, S. Bootsma, M. Bijlsma, and L. Vermeulen provide an overview of the histopathological, genomic, and transcriptomic features of peritoneal metastases and argue that peritoneal metastatic disease should be considered a distinct disease entity.

The intestinal epithelial lining is one of the most rapidly renewing cell populations in the body. As a result, the gut has been an attractive model to resolve key mechanisms in epithelial homeostasis. In particular the role of intestinal stem cells (ISCs) in the renewal process has been intensely studied. Interestingly, as opposed to the traditional stem cell theory, the ISC is not a static population but displays significant plasticity and in situations of tissue regeneration more differentiated cells can revert back to a stem cell state upon exposure to extracellular signals. Importantly, normal intestinal homeostasis provides important insight into mechanisms that drive colorectal cancer (CRC) development and growth. Specifically, the dynamics of cancer stem cells bear important resemblance to ISC functionality. In this review we present an overview of the current knowledge on ISCs in homeostasis and their role in malignant transformation. Also, we discuss the existence of stem cells in intestinal adenomas and CRC and how these cells contribute to (pre-)malignant growth. Furthermore, we will focus on new paradigms in the field of dynamical cellular hierarchies in CRC and the intimate relationship between tumor cells and their niche.

The rapid cell turnover of the intestinal epithelium is achieved from small numbers of stem cells located in the base of glandular crypts. These stem cells have been variously described as rapidly cycling or quiescent. A functional arrangement of stem cells that reconciles both of these behaviours has so far been difficult to obtain. Alternative explanations for quiescent cells have been that they act as a parallel or reserve population that replace rapidly cycling stem cells periodically or after injury; their exact nature remains unknown. Here we show mouse intestinal quiescent cells to be precursors that are committed to mature into differentiated secretory cells of the Paneth and enteroendocrine lineage. However, crucially we find that after intestinal injury they are capable of extensive proliferation and can give rise to clones comprising the main epithelial cell types. Thus, quiescent cells can be recalled to the stem-cell state. These findings establish quiescent cells as an effective clonogenic reserve and provide a motivation for investigating their role in pathologies such as colorectal cancers and intestinal inflammation. A new method to trace the lineage of slow cycling label-retaining cells (LRCs) in vivo identifies a population of LRCs that have features of committed Paneth cells but still express stem-cell markers such as Lgr5; the slow cycling cells differentiate into Paneth cells without cell division, but after injury can also repopulate the stem-cell niche and contribute to the regeneration of all intestinal lineages. Quiescent cells in intestinal epithelium Whether slowly cycling or quiescent stem cells co-exist with more rapidly cycling stem cells in the intestinal crypt is a matter of intense debate. Using a new method to trace the lineage of slowly cycling label-retaining cells (LRCs) in vivo , Douglas Winton and colleagues have identified a population of LRCs that has features of committed Paneth cells but still expresses stem cell markers such as Lgr5. The slowly cycling cells differentiate into Paneth cells without cell division, but in response to injury, they can also repopulate the stem cell niche and contribute to the regeneration of the all intestinal lineages. This work suggests that quiescent cells do act as a clonogenic reserve that could play a part in the pathology of intestinal cancers and inflammation.

Molecular subtyping of cancer is a critical step towards more individualized therapy and provides important biological insights into cancer heterogeneity. Although gene expression signature-based classification has been widely demonstrated to be an effective approach in the last decade, the widespread implementation has long been limited by platform differences, batch effects, and the difficulty to classify individual patient samples. Here, we describe a novel supervised cancer classification framework, deep cancer subtype classification (DeepCC), based on deep learning of functional spectra quantifying activities of biological pathways. In two case studies about colorectal and breast cancer classification, DeepCC classifiers and DeepCC single sample predictors both achieved overall higher sensitivity, specificity, and accuracy compared with other widely used classification methods such as random forests (RF), support vector machine (SVM), gradient boosting machine (GBM), and multinomial logistic regression algorithms. Simulation analysis based on random subsampling of genes demonstrated the robustness of DeepCC to missing data. Moreover, deep features learned by DeepCC captured biological characteristics associated with distinct molecular subtypes, enabling more compact within-subtype distribution and between-subtype separation of patient samples, and therefore greatly reduce the number of unclassifiable samples previously. In summary, DeepCC provides a novel cancer classification framework that is platform independent, robust to missing data, and can be used for single sample prediction facilitating clinical implementation of cancer molecular subtyping.

Cancer is a disease in which cells accumulate genetic aberrations that are believed to confer a clonal advantage over cells in the surrounding tissue. However, the quantitative benefit of frequently occurring mutations during tumor development remains unknown. We quantified the competitive advantage of Ape loss, Kras activation, and P53 mutations in the mouse intestine. Our findings indicate that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wild-type stem cells after biased, but still stochastic events. Furthermore, P53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene are favored. Our work confirms the previously theoretical notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages.