bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–10–06
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Tuft cells act as regenerative stem cells in the human intestine.
  2. Dietary and metabolic effects on intestinal stem cells in health and disease.
  3. p21 Regulates Wnt-Notch balance via DREAM/MMB/Rb-E2F1 and maintains intestinal stem cell homeostasis.
  4. Fructose shields human colorectal cancer cells from hypoxia-induced necroptosis.
  5. Age-Dependent Differences in Radiation-Induced DNA Damage Responses in Intestinal Stem Cells.
  6. CD44: A Stemness Driver, Regulator and Marker - all in one?
  7. Organization of a cytoskeletal superstructure in the apical domain of intestinal tuft cells.
  8. Charting the metabolic biogeography of the colorectum in cancer: challenging the right sided versus left sided classification.
  9. Mimicking and analyzing the tumor microenvironment.
  10. Protocol to calculate the synergy of drug combinations in organoids and primary cells from murine tumors.
  1. Nature. 2024 Oct 02.
    Tuft cells act as regenerative stem cells in the human intestine.
    Lulu Huang, Jochem H Bernink, Amir Giladi, Daniel Krueger, Gijs J F van Son, Maarten H Geurts, Georg Busslinger, Lin Lin, Harry Begthel, Maurice Zandvliet, Christianne J Buskens, Willem A Bemelman, Carmen López-Iglesias, Peter J Peters, Hans Clevers.
      In mice, intestinal tuft cells have been described as a long-lived, postmitotic cell type. Two distinct subsets have been identified: tuft-1 and tuft-2 (ref. 1). By combining analysis of primary human intestinal resection material and intestinal organoids, we identify four distinct human tuft cell states, two of which overlap with their murine counterparts. We show that tuft cell development depends on the presence of Wnt ligands, and that tuft cell numbers rapidly increase on interleukin-4 (IL-4) and IL-13 exposure, as reported previously in mice2-4. This occurs through proliferation of pre-existing tuft cells, rather than through increased de novo generation from stem cells. Indeed, proliferative tuft cells occur in vivo both in fetal and in adult human intestine. Single mature proliferating tuft cells can form organoids that contain all intestinal epithelial cell types. Unlike stem and progenitor cells, human tuft cells survive irradiation damage and retain the ability to generate all other epithelial cell types. Accordingly, organoids engineered to lack tuft cells fail to recover from radiation-induced damage. Thus, tuft cells represent a damage-induced reserve intestinal stem cell pool in humans.
    DOI:  https://doi.org/10.1038/s41586-024-07952-6
  2. Nat Rev Gastroenterol Hepatol. 2024 Oct 02.
    Dietary and metabolic effects on intestinal stem cells in health and disease.
    Jessica E S Shay, Ömer H Yilmaz.
      Diet and nutritional metabolites exhibit wide-ranging effects on health and disease partly by altering tissue composition and function. With rapidly rising rates of obesity, there is particular interest in how obesogenic diets influence tissue homeostasis and risk of tumorigenesis; epidemiologically, these diets have a positive correlation with various cancers, including colorectal cancer. The gastrointestinal tract is a highly specialized, continuously renewing tissue with a fundamental role in nutrient uptake and is, in turn, influenced by diet composition and host metabolic state. Intestinal stem cells are found at the base of the intestinal crypt and can generate all mature lineages that comprise the intestinal epithelium and are uniquely influenced by host diet, metabolic by-products and energy dynamics. Similarly, tumour growth and metabolism can also be shaped by nutrient availability and host diet. In this Review, we discuss how different diets and metabolic changes influence intestinal stem cells in homeostatic and pathological conditions, as well as tumorigenesis. We also discuss how dietary changes and composition affect the intestinal epithelium and its surrounding microenvironment.
    DOI:  https://doi.org/10.1038/s41575-024-00980-7
  3. Cell Death Discov. 2024 Sep 28. 10(1): 413
    p21 Regulates Wnt-Notch balance via DREAM/MMB/Rb-E2F1 and maintains intestinal stem cell homeostasis.
    Liangxia Jiang, Jie Tian, Jun Yang, Ronggang Luo, Yongjin Zhang, Chihao Shao, Bing Guo, Xiaoming Wu, Juhua Dan, Ying Luo.
      The crosstalk and balance regulation of Wnt-Notch have been known to be essential for cell fate decision and tissue regeneration, however, how this balance is maintained and how the Wnt-Notch pathways are connected with cell cycle regulation is still not clear. By analyzing the molecular alterations in mouse model with accelerated aging phenotypes due to loss of p21 function in a Werner syndrome background, we observed that Wnt3 and β-Catenin were down-regulated, while Notch1 and Hes1 were up-regulated. This disruption in Wnt-Notch signaling was accompanied by the loss of intestinal stem cell compartment, increase in Bmi1 positive cells, loss of Olfm4/Lgr5 positive cells, and reduced secretory Paneth cells and goblet cells in the intestinal crypts of p21TKO mice. BrdU incorporation, cleaved caspase 3, and Tunel assay results revealed the fast turnover of intestinal epithelia, which may result in abnormal stem cell mobilization and exhaustion of the stem cell reservoir in the intestinal crypts. We further identified shift of DREAM complex towards MMB complex due to the loss of p21 as the cause for faster turnover of intestinal epithelia. Importantly, we identified the E2F1 as the transcriptional regulator for Notch1, which linked the p21-DREAM/MMB/Rb-E2F1 pathway with Wnt-Notch pathway. The overexpression of p21 rescued the DREAM pathway, as well as the imbalance of Wnt-Notch pathway. In summary, our data identify p21 as an important factor in maintaining sequential mobilization, proliferation, and homeostasis of intestinal stem cells.
    DOI:  https://doi.org/10.1038/s41420-024-02192-z
  4. NPJ Sci Food. 2024 Oct 01. 8(1): 71
    Fructose shields human colorectal cancer cells from hypoxia-induced necroptosis.
    Xiang-Han Huang, Ching-Ying Huang.
      Recent studies have shown that high dietary fructose intake enhances intestinal tumor growth in mice. Our previous work indicated that glucose enables hypoxic colorectal cancer (CRC) cells to resist receptor-interacting protein (RIP)-dependent necroptosis. Despite having the same chemical formula, glucose and fructose are absorbed through different transporters yet both can enter the glycolytic metabolic pathway. The excessive intake of dietary fructose, leading to its overflow into the colon, allows colonic cells to absorb fructose apically. This study explores the mechanisms behind apical fructose-mediated death resistance in CRC cells under hypoxic stress. Utilizing three CRC cell lines (Caco-2, HT29, and T84) under normoxic and hypoxic conditions with varying fructose concentrations, we assessed lactate dehydrogenase (LDH) activity, RIP1/3 complex formation (a necroptosis marker), and cell integrity. We investigated the role of fructose in glycolytic-mediated death resistance using glycolytic inhibitors iodoacetate (IA, a glycolytic inhibitor to glyceraldehyde 3-phosphate dehydrogenase), and UK5099 (UK, an inhibitor to mitochondrial pyruvate carrier). Our findings reveal that apical fructose prevents the hypoxia-induced RIP-dependent necroptosis in Caco-2 and HT29 cells. Fructose exposure under hypoxia also preserved epithelial integrity. IA, but not UK, blocked fructose-mediated glycolytic metabolite production and necrosis, indicating that anaerobic glycolytic metabolites facilitate death resistance. Notably, fructose treatment upregulated pyruvate kinase (PK)-M1 mRNA in hypoxic Caco-2 and HT29 cells, while PKM2 upregulation was exclusive to HT29 cells. In conclusion, apical fructose utilization through glycolysis effectively inhibits hypoxia-induced RIP-dependent necroptosis in CRC cells, shedding light on potential metabolic adaptation mechanisms in the tumor microenvironment and suggesting novel targets for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41538-024-00318-2
  5. Int J Mol Sci. 2024 Sep 23. pii: 10213. [Epub ahead of print]25(18):
    Age-Dependent Differences in Radiation-Induced DNA Damage Responses in Intestinal Stem Cells.
    Guanyu Zhou, Tsutomu Shimura, Taiki Yoneima, Akiko Nagamachi, Akinori Kanai, Kazutaka Doi, Megumi Sasatani.
      Age at exposure is a critical modifier of the risk of radiation-induced cancer. However, the effects of age on radiation-induced carcinogenesis remain poorly understood. In this study, we focused on tissue stem cells using Lgr5-eGFP-ires-CreERT2 mice to compare radiation-induced DNA damage responses between Lgr5+ and Lgr5- intestinal stem cells. Three-dimensional immunostaining analyses demonstrated that radiation induced apoptosis and the mitotic index more efficiently in adult Lgr5- stem cells than in adult Lgr5+ stem cells but not in infants, regardless of Lgr5 expression. Supporting this evidence, rapid and transient p53 activation occurred after irradiation in adult intestinal crypts but not in infants. RNA sequencing revealed greater variability in gene expression in adult Lgr5+ stem cells than in infant Lgr5+ stem cells after irradiation. Notably, the cell cycle and DNA repair pathways were more enriched in adult stem cells than in infant stem cells after irradiation. Our findings suggest that radiation-induced DNA damage responses in mouse intestinal crypts differ between infants and adults, potentially contributing to the age-dependent susceptibility to radiation carcinogenesis.
    Keywords:  DNA damage response; DNA repair; Lgr5+ intestinal stem cells; age at exposure; apoptosis; cell cycle; gene expression variability; intestinal crypts; p53 activation; radiation; stem cell
    DOI:  https://doi.org/10.3390/ijms251810213
  6. Stem Cells. 2024 Oct 04. pii: sxae060. [Epub ahead of print]
    CD44: A Stemness Driver, Regulator and Marker - all in one?
    Steffen J Sonnentag, Nagwa S M Ibrahim, Veronique Orian-Rousseau.
      Although the concept of cancer stem cells is still controversial, previous studies have shown that blood cancers, as well as specific types of solid cancers such as colorectal cancer, rely on stem cells during the onset of tumor growth and further tumor development. Moreover, resistance to therapeutic treatment in leukemias such as acute myeloid leukemia and in colorectal cancer can be attributed to a small population of cells with stemness properties known as minimal residual disease. In this review, we look back on the discovery of cancer stem cells and the contribution of the findings in blood cancer to a parallel discovery in solid cancers. We focus on CD44 as a stem cell marker, both in blood cancers and in several types of solid cancers, particularly of the gastro-intestinal tract. This review highlights newly discovered molecular mechanisms of action of CD44 which indicate that CD44 has indeed a function in stemness, stem cell maintenance and drug resistance. We attempt here to make the link between the functions of CD44 isoforms in stemness and their involvement in specific steps of tumor growth and metastasis.
    DOI:  https://doi.org/10.1093/stmcls/sxae060
  7. J Cell Biol. 2024 Dec 02. pii: e202404070. [Epub ahead of print]223(12):
    Organization of a cytoskeletal superstructure in the apical domain of intestinal tuft cells.
    Jennifer B Silverman, Evan E Krystofiak, Leah R Caplan, Ken S Lau, Matthew J Tyska.
      Tuft cells are a rare epithelial cell type that play important roles in sensing and responding to luminal antigens. A defining morphological feature of this lineage is the actin-rich apical "tuft," which contains large fingerlike protrusions. However, details of the cytoskeletal ultrastructure underpinning the tuft, the molecules involved in building this structure, or how it supports tuft cell biology remain unclear. In the context of the small intestine, we found that tuft cell protrusions are supported by long-core bundles that consist of F-actin crosslinked in a parallel and polarized configuration; they also contain a tuft cell-specific complement of actin-binding proteins that exhibit regionalized localization along the bundle axis. Remarkably, in the sub-apical cytoplasm, the array of core actin bundles interdigitates and co-aligns with a highly ordered network of microtubules. The resulting cytoskeletal superstructure is well positioned to support subcellular transport and, in turn, the dynamic sensing functions of the tuft cell that are critical for intestinal homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202404070
  8. Mol Cancer. 2024 Sep 28. 23(1): 211
    Charting the metabolic biogeography of the colorectum in cancer: challenging the right sided versus left sided classification.
    Abhishek Jain, Montana T Morris, Domenica Berardi, Trisha Arora, Xavier Domingo-Almenara, Philip B Paty, Nicholas J W Rattray, Daniel Kerekes, Lingeng Lu, Sajid A Khan, Caroline H Johnson.
       OBJECTIVE: Colorectal cancer (CRC) is conventionally classified as right sided, left sided, and rectal cancer. Clinicopathological, molecular features and risk factors do not change abruptly along the colorectum, and variations exist even within the refined subsites, which may contribute to inconsistencies in the identification of clinically relevant CRC biomarkers. We generated a CRC metabolome map to describe the association between metabolites, diagnostic and survival heterogeneity in cancers of different subsites of the colorectum.
    DESIGN: Utilizing 372 patient-matched tumor and normal mucosa tissues, liquid chromatography-mass spectrometry was applied to examine metabolomic profiles along seven subsites of the colorectum: cecum (n = 63), ascending colon (n = 44), transverse colon (n = 32), descending colon (n = 28), sigmoid colon (n = 75), rectosigmoid colon (n = 38), and rectum (n = 92).
    RESULTS: 39 and 70 significantly altered metabolites (including bile acids, lysophosphatidylcholines and lysophosphatidylethanolamines) among tumors and normal mucosa, respectively, showed inter-subsite metabolic heterogeneity between CRC subsites. Gradual changes in metabolite abundances with significantly linear trends from cecum to rectum were observed: 23 tumor-specific metabolites, 30 normal mucosa-specific metabolites, and 15 metabolites in both tumor and normal mucosa, had concentration gradients across the colorectum, and is disease status dependent. The metabolites that showed a linear trend included bile acids, amino acids, lysophosphatidylcholines, and lysophosphatidylethanolamines. Comparison of tumors to patient-matched normal mucosa revealed metabolite changes exclusive to each subsite, thereby further highlighting differences in cancer metabolism across the 7 subsites of the colorectum. Furthermore, metabolites associated with survival were different and unique to each subsite. Finally, an interactive and publicly accessible CRC metabolome database was designed to enable access and utilization of this rich data resource ( https://colorectal-cancer-metabolome.com/yale-university ).
    CONCLUSIONS: Gradual changes exist in metabolite abundances from the cecum to the rectum. The association between patient survival and distinct metabolites with anatomic subsite of the colorectum, reveals differences between cancers across the colorectum. These inter-subsite metabolic heterogeneities enrich the current understanding and substantiate previous studies that have challenged the conventional classification of right-sided, left-sided, and rectal cancers, by identifying specific metabolites that offer new biological insights into CRC subsite heterogeneity. The database designed in this study will enable researchers to delve into granular information on the CRC metabolome, which until now has not been available.
    Keywords:  Biomarkers; Colorectal cancer; Metabolome database; Metabolomics; Subsite heterogeneity
    DOI:  https://doi.org/10.1186/s12943-024-02133-5
  9. Cell Rep Methods. 2024 Sep 25. pii: S2667-2375(24)00244-3. [Epub ahead of print] 100866
    Mimicking and analyzing the tumor microenvironment.
    Roxane Crouigneau, Yan-Fang Li, Jamie Auxillos, Eliana Goncalves-Alves, Rodolphe Marie, Albin Sandelin, Stine Falsig Pedersen.
      The tumor microenvironment (TME) is increasingly appreciated to play a decisive role in cancer development and response to therapy in all solid tumors. Hypoxia, acidosis, high interstitial pressure, nutrient-poor conditions, and high cellular heterogeneity of the TME arise from interactions between cancer cells and their environment. These properties, in turn, play key roles in the aggressiveness and therapy resistance of the disease, through complex reciprocal interactions between the cancer cell genotype and phenotype, and the physicochemical and cellular environment. Understanding this complexity requires the combination of sophisticated cancer models and high-resolution analysis tools. Models must allow both control and analysis of cellular and acellular TME properties, and analyses must be able to capture the complexity at high depth and spatial resolution. Here, we review the advantages and limitations of key models and methods in order to guide further TME research and outline future challenges.
    Keywords:  CP: Biotechnology; CP: Cancer biology; cancer; heterogeneity; metabolism; microfluidics; organoids; tumor microenvironment; tumor models
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100866
  10. STAR Protoc. 2024 Oct 01. pii: S2666-1667(24)00519-7. [Epub ahead of print]5(4): 103354
    Protocol to calculate the synergy of drug combinations in organoids and primary cells from murine tumors.
    David Eisenbarth, Bomin Ku, Dae-Sik Lim.
      Evaluating the synergy of drug combinations is crucial in advancing treatment regimens. Here, we present a protocol to establish primary cells and organoids from murine tumors and calculate drug synergy. We describe all necessary cell culture procedures, including establishing primary cultures, setting up treatment groups, and detecting cell viability. We then outline how to calculate the synergy score based on a bioinformatical pipeline. This approach applies to any disease model in which a combination of drugs needs to be evaluated. For complete details on the use and execution of this protocol, please refer to Ku et al.1.
    Keywords:  Cancer; Cell-based Assays; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2024.103354
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