The undulating topography of the intestinal epithelium creates regionalized homeostatic niches at the base of each crypt, with each niche supporting neutrally evolving oligoclonal stem cell populations. At the crypt base, the fate of stem cell progeny is tightly regulated by intercompartmental polarized morphogenetic gradients, which converge to instruct continuous, but controlled, epithelial-cell turnover. To initiate tumorigenesis, a neoplastic clone must defy or escape such morphogenetic constraints either by outcompeting neighbouring stem cells or by establishing an ectopic stem cell population de novo. The position of the cell-of-origin within the crypt thus determines the oncogenic mechanisms required to subvert local homeostatic control. In turn, this defines the route of carcinogenesis and underpins the pervasive heterogeneity of colorectal cancers. Here, we explore the relationship between the position of the cell-of-origin on the vertical crypt axis and the cell plasticity mechanisms co-opted and corrupted to escape homeostatic control. We consider how this influences clonal dynamics at the pre-cancer stage and initiates distinct carcinogenesis pathways engendering morphologically discrete precursor lesions. Finally, we discuss how such lesions progress to molecularly heterogeneous subtypes with distinct clinicopathological features and therapeutic outcomes, and how phenotypic, rather than just genotypic, heterogeneity promotes tumour-cell adaptation, therapeutic resistance and metastasis. This Review by Sphyris et al. discusses how the cell-of-origin determines the route of colorectal carcinogenesis and how phenotypic plasticity and heterogeneity shape tumour evolution, disease recurrence, metastatic competence and response to therapy.
Ye et al. show that ischaemic stroke can drive glioma progression through microenvironmental remodelling of tumour-associated astrocytes.
Single-cell genomics has entered the field of cancer research and clinical oncology, enhancing our understanding of the somatic evolution of cancer and intra-tumour genomic heterogeneity. The evolutionary history of a tumour can be represented as a phylogenetic tree, and in recent years, multiple statistical and computational methods have been proposed to reconstruct tumour phylogenies from single-cell sequencing data. The nature of tumour evolution and of single-cell sequencing, however, raises new challenges in modelling the data and the underlying evolutionary processes that are not addressed by classical phylogenetic and phylodynamic approaches. Here, we review the models and assumptions behind bespoke single-cell tumour phylogeny methods, along with recent computational and algorithmic advances in phylogenetic inference. We discuss the role these advances have in basic and clinical oncology research, and how they provide new insights into individual cancers and cohorts of patient samples. We conclude with an outlook of current challenges for single-cell phylogenetics and potential future applications. Single-cell sequencing has transformed the study of tumour evolution by enabling high-resolution reconstruction of cancer phylogenies. This Review discusses the models, assumptions and computational approaches underlying single-cell tumour phylogeny inference, and it highlights emerging applications in cancer biology, patient stratification and evolutionary forecasting.
Theranostics refers to the inseparable combination of disease diagnosis and therapy, with the former critically guiding the selection, application and outcome of the latter. In oncology, theranostics traditionally encompass radiolabelled peptides for in vivo molecular imaging of receptor expression by cancer cells, followed by radionuclide treatment using the same peptides labelled with β-emitting radioisotopes. Here we provide an overview of the basic principles and current clinical practice of theranostic probes and protocols, and we expand the terminology to include locally and systemically applied nanotheranostics and microtheranostics, as well as imaging-guided surgical interventions. Building on solid progress in target identification, probe design and hardware development, as well as on promising recent results achieved in clinical trials, we foresee a bright and broad future for multiscale theranostics, for the treatment of oncological pathologies and beyond. Theranostics integrates diagnostic imaging with targeted therapy to enhance cancer treatment. In this Review, Sofias et al. discuss recent advances in radiotheranostic strategies, advances in nanotheranostic and microtheranostic platforms, and image-guided therapeutic and surgical interventions in oncology.
In a recent study, García-Gómez et al. identify an adaptive proliferative pause program that supports the survival of micrometastatic cells during early brain colonization and uncover therapeutic opportunities to target this state.
