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The Leedham lab have developed a new tool that assesses the relative enrichment of two main types of cancer stem cells in colorectal cancer, which may help to guide therapy selection in the future.

The molecular and morphological markers of Crypt base columnar (CBC) stem cell signature (Lgr5+, Anxa1-, Sca1-) and Regenerative stem cell (RSC) signature (Lgr5-, Anza1-, Sca1+) are analysed using the stem cell index to identify the level of BCB relative to RSC enrichment. In intestinal tumours, this mixture influences (1) tumour phenotype (genotype clustering in mice and single cell phenotype and subtype clustering in humans), (2) tumour signalling (signalling pathways and organoid manipulation in mice and mutation selection and signalling pathways in humans) and (3) tumour selection pressure (stem cell ablation in mice and chemotherapeutic impact in humans). © The authors 2022

Stem cells are long-lived cells that can respond to environmental cues and allow our organs to regenerate. Thanks to stem cells, the lining of the intestine for example fully renews every 4-5 days maintaining homeostasis. However, when stem cells acquire mutations, they can, over time, develop into cancers, and it is cancer stem cells that are responsible for the uncontrolled growth seen in cancers.

In a recent publication in Cell Stem Cell, Oxford researchers Ester Gil Vasquez, Nadia Nasreddin and colleagues developed a tool to identify distinct ‘varieties’ of stem cells in the intestine. In particular they focused on LGR5-positive crypt-based columnar stem cells (CBCs) and LGR5-negative regenerative stem cell (RSC) populations, and noted that different tumours had varying proportions of these two types of stem cell. By examining tissues from both mice and humans, they observed that the mixture of CBCs and RBCs was associated with distinct cancer-relevant mutations. Even when the stem cell niche was experimentally perturbed, local tumour signalling was able to restore the stem cell ‘equilibrium’, and this adaptability of the tumour stem cell populations was associated with poor response to chemotherapy. The team believe that they can use their new tool to assess how different tumours respond to different chemotherapies and use this measurement to help direct treatment choices.

 

We have shown that different colorectal cancers are maintained by more than one population of stem cells. We have developed a simple molecular tool to identify the relative mix of stem cell populations in cancers, and can use this to measure the dynamic impact of different drug treatments on these cancer stem cell types. We believe that these measurements will allow us to assess the tumour response to a particular therapy and may help us make better, biologically-informed, decisions about the type and schedule of chemotherapies in this common cancer. - Senior author Simon Leedham, Professor of Molecular and Population Genetics and a Wellcome Senior Research Fellow in Clinical Science

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