bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023–11–05
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion.
  2. Microbial-dependent recruitment of immature myeloid cells promotes intestinal regeneration.
  3. A tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development.
  4. MAP kinase ERK5 modulates cancer cell sensitivity to extrinsic apoptosis induced by death-receptor agonists.
  5. P53‑microRNA interactions regulate the response of colorectal tumor cells to oxaliplatin under normoxic and hypoxic conditions.
  6. Single-cell RNA sequencing of intestinal crypts reveals vital events in damage repair and the double-edged sword effect of the Wnt3/β-catenin pathway in irradiated mice.
  7. Optogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation.
  8. Reactivation of embryonic genetic programs in tissue regeneration and disease.
  9. Photodynamic therapy augments oxaliplatin-induced immunogenic cell death in colorectal cancer.
  10. HER-3 surface expression increases in advanced colorectal cancer representing a potential therapeutic target.
  1. Proc Natl Acad Sci U S A. 2023 Nov 07. 120(45): e2306476120
    IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion.
    Alberto Dinarello, Makenna May, Jesus Amo-Aparicio, Tania Azam, Joseph M Gaballa, Carlo Marchetti, Annachiara Tesoriere, Rachele Ghirardo, Jasmina S Redzic, William S Webber, Shaikh M Atif, Suzhao Li, Elan Z Eisenmesser, Dennis M de Graaf, Charles A Dinarello.
      The IL-1 Family member IL-38 has been characterized primarily as an antiinflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL-38 in the murine small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL-38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL-38-deficient mice develop more slowly. This reduction in size is likely due to the downregulation of intestinal stemness markers (i.e., Fzd5, Ephb2, and Olfm4) expression compared with wild-type organoids. The IL-38 binding to IL-1R6 and IL-1R9 is still a matter of debate. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL-1R9-deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL-38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL-38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild-type mice, IL-38 stimulation induced low concentrations of IL-1β which contribute to organoid growth. However, high concentrations of IL-1β have detrimental effects on the cultures that were prevented by treatment with recombinant IL-38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an antiinflammatory molecule in the SI, maintaining homeostasis.
    Keywords:  gastroenterology; inflammation; interleukin
    DOI:  https://doi.org/10.1073/pnas.2306476120
  2. Cell Mol Gastroenterol Hepatol. 2023 Oct 26. pii: S2352-345X(23)00186-8. [Epub ahead of print]
    Microbial-dependent recruitment of immature myeloid cells promotes intestinal regeneration.
    Zhengyu Jiang, Quin T Waterbury, Ermanno Malagola, Na Fu, Woosook Kim, Yosuke Ochiai, Feijing Wu, Chandan Guha, Carrie J Shawber, Kelley S Yan, Timothy C Wang.
       BACKGROUND & AIMS: The intestinal epithelium functions both in nutrient absorption and as a barrier, separating the luminal contents from a network of vascular, fibroblastic, and immune cells underneath. Following injury to the intestine, multiple cell populations cooperate to drive regeneration of the mucosal barrier, including lymphatic endothelial cells (LECs). A population of granulocytic immature myeloid cells (IMCs), marked by histidine decarboxylase (Hdc), participate in regeneration of multiple organs such as the colon and central nervous system, but their contribution to intestinal regeneration was unknown.
    METHODS: Using male and female HdcGFP mice, we investigated the role of Hdc+ IMCs in intestinal regeneration after exposure to 12 Gy whole-body irradiation. The movement of IMCs was analyzed using flow cytometry and immunostaining. Ablation of Hdc+ cells using HdcCreERT2; R26DTA tamoxifen-inducible recombinase Cre system, conditional knockout of Ptgs2 in Hdc+ cells using HdcCre; Ptgs2fl/fl mice, and visualization of LECs using Prox1tdTomato mice was also performed. The role of microbial signals was investigated by knocking down mice's gut microbiomes using antibiotic cocktail gavages.
    RESULTS: We found that Hdc+ IMCs infiltrate the injured intestine following irradiation injury and promote epithelial regeneration in part by modulating LEC activity. Hdc+ IMCs express Ptgs2 (encoding COX-2), enables them to produce prostaglandin E2 (PGE2). PGE2 acts upon the EP4 receptor on LECs to promote lymphangiogenesis and induce the expression of pro-regenerative factors including RSPO3. Depletion of gut microbes leads to reduced intestinal regeneration by impaired recruitment of IMCs.
    CONCLUSIONS: Altogether, our results unveil a critical role for IMCs in intestinal repair by modulating LEC activity and implicate gut microbes as mediators of intestinal regeneration.
    Keywords:  PGE2; RSPO3; endothelial cell; microbiome; myeloid
    DOI:  https://doi.org/10.1016/j.jcmgh.2023.10.007
  3. Nat Commun. 2023 10 28. 14(1): 6872
    A tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development.
    Ryan N O'Keefe, Annalisa L E Carli, David Baloyan, David Chisanga, Wei Shi, Shoukat Afshar-Sterle, Moritz F Eissmann, Ashleigh R Poh, Bhupinder Pal, Cyril Seillet, Richard M Locksley, Matthias Ernst, Michael Buchert.
      Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.
    DOI:  https://doi.org/10.1038/s41467-023-42215-4
  4. Cell Death Dis. 2023 Nov 02. 14(11): 715
    MAP kinase ERK5 modulates cancer cell sensitivity to extrinsic apoptosis induced by death-receptor agonists.
    Sergio Espinosa-Gil, Saska Ivanova, Elisenda Alari-Pahissa, Melek Denizli, Beatriz Villafranca-Magdalena, Maria Viñas-Casas, Idoia Bolinaga-Ayala, Andrés Gámez-García, Claudia Faundez-Vidiella, Eva Colas, Miguel Lopez-Botet, Antonio Zorzano, José Miguel Lizcano.
      Death receptor ligand TRAIL is a promising cancer therapy due to its ability to selectively trigger extrinsic apoptosis in cancer cells. However, TRAIL-based therapies in humans have shown limitations, mainly due inherent or acquired resistance of tumor cells. To address this issue, current efforts are focussed on dissecting the intracellular signaling pathways involved in resistance to TRAIL, to identify strategies that sensitize cancer cells to TRAIL-induced cytotoxicity. In this work, we describe the oncogenic MEK5-ERK5 pathway as a critical regulator of cancer cell resistance to the apoptosis induced by death receptor ligands. Using 2D and 3D cell cultures and transcriptomic analyses, we show that ERK5 controls the proteostasis of TP53INP2, a protein necessary for full activation of caspase-8 in response to TNFα, FasL or TRAIL. Mechanistically, ERK5 phosphorylates and induces ubiquitylation and proteasomal degradation of TP53INP2, resulting in cancer cell resistance to TRAIL. Concordantly, ERK5 inhibition or genetic deletion, by stabilizing TP53INP2, sensitizes cancer cells to the apoptosis induced by recombinant TRAIL and TRAIL/FasL expressed by Natural Killer cells. The MEK5-ERK5 pathway regulates cancer cell proliferation and survival, and ERK5 inhibitors have shown anticancer activity in preclinical models of solid tumors. Using endometrial cancer patient-derived xenograft organoids, we propose ERK5 inhibition as an effective strategy to sensitize cancer cells to TRAIL-based therapies.
    DOI:  https://doi.org/10.1038/s41419-023-06229-6
  5. Oncol Rep. 2023 Dec;pii: 219. [Epub ahead of print]50(6):
    P53‑microRNA interactions regulate the response of colorectal tumor cells to oxaliplatin under normoxic and hypoxic conditions.
    Jiayu Zhang, Chenguang Li, Luanbiao Sun, Denghua Sun, Tiancheng Zhao.
      Oxaliplatin (OXA)‑containing regimens are used as first‑line chemotherapy in colorectal cancer (CRC). However, OXA resistance remains a major challenge in CRC treatment. CRC cells that adapt to hypoxia can potentially develop OXA resistance, and the underlying molecular mechanisms still need to be further investigated. In the current study, the OXA drug sensitivity of two CRC cell lines, HCT116 (TP53WT) and HT29 (TP53MT), was compared under both normoxic and hypoxic conditions. It was found that under normoxic condition, HCT116 cells showed significantly higher OXA sensitivity than HT29 cells. However, both cell lines showed remarkable OXA resistance under hypoxic conditions. It was also revealed that P53 levels were increased after OXA and hypoxia treatment in HCT116 cells but not in HT29 cells. Notably, knocking down P53WT decreased normoxic but increased hypoxic OXA sensitivity in HCT116 cells, which did not exist in HT29 cells. Molecular analysis indicated that P53WT activated microRNA (miR)‑26a and miR‑34a in OXA treatment and activated miR‑23a in hypoxia treatment. Cell proliferation experiments indicated that a high level of miR‑23a decreased OXA sensitivity and that a high level of miR‑26a or miR‑34a increased OXA sensitivity in HCT116 cells. Additionally, it was demonstrated that miR‑26a, miR‑34a and miR‑23a affect cell apoptosis through regulation of MCL‑1, EZH2, BCL‑2, SMAD 4 and STAT3. Taken together, the present findings revealed the dual function of P53 in regulating cellular chemo‑sensitivity and highlighted the role of P53‑miR interactions in the response of CRC cells to OXA chemotherapy under normoxic and hypoxic conditions.
    Keywords:  P53; colorectal cancer; hypoxia; microRNA; oxaliplatin
    DOI:  https://doi.org/10.3892/or.2023.8656
  6. Redox Biol. 2023 Oct 25. pii: S2213-2317(23)00343-9. [Epub ahead of print]68 102942
    Single-cell RNA sequencing of intestinal crypts reveals vital events in damage repair and the double-edged sword effect of the Wnt3/β-catenin pathway in irradiated mice.
    Tong Yuan, Junling Zhang, Yue Zhao, Yuying Guo, Saijun Fan.
      In this study, we executed single-cell RNA sequencing of intestinal crypts. We analyzed the differentially expressed genes (DEGs) at different time points (the first, third, and fifth days) after 13 Gy and 15 Gy abdominal body radiation (ABR) exposure and then executed gene ontology (GO) enrichment analysis, RNA velocity analysis, cell communication analysis, and ligand‒receptor interaction analysis to explore the vital events in damage repair and the multiple effects of the Wnt3/β-catenin pathway on irradiated mice. Results from bioinformatics analysis were confirmed by a series of biological experiments. Results showed that the antibacterial response is a vital event during the damage response process after 13 Gy ABR exposure; ionizing radiation (IR) induced high heterogeneity in the transient amplification (TA) cluster, which may differentiate into mature cells and stem cells in irradiated small intestine (SI) crypts. Conducting an enrichment analysis of the DEGs between mice exposed to 13 Gy and 15 Gy ABR, we concluded that the Wnt3/β-catenin and MIF-CD74/CD44 signaling pathways may contribute to 15 Gy ABR-induced mouse death. Wnt3/β-catenin promotes the recovery of irradiated SI stem/progenitor cells, which may trigger macrophage migration inhibitory factor (MIF) release to further repair IR-induced SI injury; however, with the increase in radiation dose, activation of CD44 on macrophages provides the receptor for MIF signal transduction, initiating the inflammatory cascade response and ultimately causing a cytokine release syndrome. In contrast to previous research, we confirmed that inhibition of the Wnt3/β-catenin pathway or blockade of CD44 on the second day after 15 Gy ABR may significantly protect against ABR-induced death. This study indicates that the Wnt3/β-catenin pathway plays multiple roles in damage repair after IR exposure; we also propose a novel point that the interaction between intestinal crypt stem cells (ISCs) and macrophages through the MIF-CD74/CD44 axis may exacerbate SI damage in irradiated mice.
    Keywords:  Abdominal body radiation (ABR); Antibacterial response; Macrophage migration inhibitory factor (MIF); Wnt/β-catenin signaling pathway
    DOI:  https://doi.org/10.1016/j.redox.2023.102942
  7. Nat Commun. 2023 Oct 30. 14(1): 6929
    Optogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation.
    Kirstin Meyer, Nicholas C Lammers, Lukasz J Bugaj, Hernan G Garcia, Orion D Weiner.
      YAP is a transcriptional regulator that controls pluripotency, cell fate, and proliferation. How cells ensure the selective activation of YAP effector genes is unknown. This knowledge is essential to rationally control cellular decision-making. Here we leverage optogenetics, live-imaging of transcription, and cell fate analysis to understand and control gene activation and cell behavior. We reveal that cells decode the steady-state concentrations and timing of YAP activation to control proliferation, cell fate, and expression of the pluripotency regulators Oct4 and Nanog. While oscillatory YAP inputs induce Oct4 expression and proliferation optimally at frequencies that mimic native dynamics, cellular differentiation requires persistently low YAP levels. We identify the molecular logic of the Oct4 dynamic decoder, which acts through an adaptive change sensor. Our work reveals how YAP levels and dynamics enable multiplexing of information transmission for the regulation of developmental decision-making and establishes a platform for the rational control of these behaviors.
    DOI:  https://doi.org/10.1038/s41467-023-42643-2
  8. Nat Genet. 2023 Oct 30.
    Reactivation of embryonic genetic programs in tissue regeneration and disease.
    Hassan Fazilaty, Konrad Basler.
      Embryonic genetic programs are reactivated in response to various types of tissue damage, providing cell plasticity for tissue regeneration or disease progression. In acute conditions, these programs remedy the damage and then halt to allow a return to homeostasis. In chronic situations, including inflammatory diseases, fibrosis and cancer, prolonged activation of embryonic programs leads to disease progression and tissue deterioration. Induction of progenitor identity and cell plasticity, for example, epithelial-mesenchymal plasticity, are critical outcomes of reactivated embryonic programs. In this Review, we describe molecular players governing reactivated embryonic genetic programs, their role during disease progression, their similarities and differences and lineage reversion in pathology and discuss associated therapeutics and drug-resistance mechanisms across many organs. We also discuss the diversity of reactivated programs in different disease contexts. A comprehensive overview of commonalities between development and disease will provide better understanding of the biology and therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41588-023-01526-4
  9. Cent Eur J Immunol. 2023 ;48(3): 189-202
    Photodynamic therapy augments oxaliplatin-induced immunogenic cell death in colorectal cancer.
    Xiaobo Wang, Lei Ren, Linhan Ye, Jing Cao.
      Colorectal cancer is one of the most frequently diagnosed cancers. Immunotherapy has been proven to be a potential treatment option for colorectal cancer. Colorectal cancer maintains immune escape by expressing low immunogenicity and following the tolerogenic cell death pathway. There is also emerging evidence that oxaliplatin and photodynamic therapy (PDT) can promote anti-tumor immunity. However, the effect of PDT combined with oxaliplatin on colorectal cancer remains elusive. Here, we analyzed the viability of HCT116 and DLD-1 cell lines after treatment with the combination of PDT and oxaliplatin. We found that the viability decreased significantly after the combination treatment. Meanwhile, we also detected that sinoporphyrin sodium (DVDMS)-derived PDT could amplify oxaliplatin-induced immunogenic cell death (ICD) in different colorectal cancer cell lines. More importantly, the combination of DVDMS-derived PDT and oxaliplatin presented strong immunogenic potential in immunocompetent BALB/c mice in the vaccination assay. Taken together, our data demonstrated that the combination of DVDMS-derived PDT and oxaliplatin is a potential novel therapy for colorectal cancer.
    Keywords:  autophagy; colorectal cancer; immunogenic cell death; oxaliplatin; photodynamic therapy
    DOI:  https://doi.org/10.5114/ceji.2023.132053
  10. Cell Death Discov. 2023 Oct 28. 9(1): 400
    HER-3 surface expression increases in advanced colorectal cancer representing a potential therapeutic target.
    Emily Capone, Thordur Tryggvason, Ilaria Cela, Beatrice Dufrusine, Morena Pinti, Francesco Del Pizzo, Helga Sigrun Gunnarsdottir, Tommaso Grottola, Vincenzo De Laurenzi, Stefano Iacobelli, Rossano Lattanzio, Gianluca Sala.
      HER-3 (also known as ErbB-3) is a human epidermal growth factor receptor tyrosine kinases family member, and its expression in CRC (colorectal cancer) tissues was previously associated with poor prognosis. In this study, HER-3 expression was analyzed by immunohistochemistry in two cohorts of early and advanced metastatic CRC patients. The first cohort included 180 patients diagnosed with CRC in absence of lymph nodes or distant metastases (Stage I and Stage II), while the second was obtained from 53 advanced metastatic CRC patients who developed synchronous (SM) and metachronous (MM) liver metastases. In the first early-stage CRC cohort, 86 out of 180 (47.8%) tumors showed membranous expression of HER-3, with a mean percentage of positive tumor cells of 25.7%; conversely, in advanced metastatic CRC primary tumors, HER-3 was detected in all specimens, with a mean percentage of positive tumor cells of 76.1%. Kaplan-Meier curves showed that in the advanced metastatic CRC group, patients with HER-3high tumors had a significantly lower Cancer-Specific Survival (CSS) rate compared to patients with HER-3low tumors (p = 0.021). Importantly, this worse CSS rate was observed only in the MM subgroup of patients with HER-3high tumors (p = 0.002). Multivariate analysis confirmed that high HER-3 expression represents a significant and strong risk factor for death in patients developing MM liver metastases (Hazard Ratio = 64.9; 95% Confidence Interval, 4.7-886.6; p = 0.002). In addition, using a specific anti-HER-3 antibody-drug conjugate, named EV20/MMAF, we showed that HER-3 + CRC cells can be efficiently targeted in vitro and in vivo. Overall, this study confirms that surface HER-3 is highly expressed in CRC and reveals that HER-3 expression increases in metastatic CRC patients compared to early stage. Importantly, the results suggest that HER-3 has a prognostic and therapeutic value in patients developing MM liver metastases.
    DOI:  https://doi.org/10.1038/s41420-023-01692-8
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