bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–06–02
twelve papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation.
  2. Mechanisms of metastatic colorectal cancer.
  3. Protocol for generation of and high-throughput drug testing with patient-derived colorectal cancer organoids.
  4. 5-Fluorouracil resistant CRC cells derived exosomes promote cancer-associated fibroblasts secreting more CXCL12.
  5. Advancements in combining targeted therapy and immunotherapy for colorectal cancer.
  6. Stem-cell states converge in multistage cutaneous squamous cell carcinoma development.
  7. The Potential Role of Intestinal Stem Cells and Microbiota for the Treatment of Colorectal Cancer.
  8. A connection between phosphatidylinositol 5-phosphate and the Hippo pathway to prevent epithelial-mesenchymal transition in cancer.
  9. Pro-inflammatory T cells-derived cytokines enhance the maturation of the human fetal intestinal epithelial barrier.
  10. TCF7L1 regulates colorectal cancer cell migration by repressing GAS1 expression.
  11. No mutation, tumour initiation.
  12. Identification of epigenetic silencing of the SFRP2 gene in colorectal cancer as a clinical biomarker and molecular significance.
  1. Dev Cell. 2024 May 23. pii: S1534-5807(24)00299-5. [Epub ahead of print]
    Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation.
    Hiroto Kinoshita, Anxo Martinez-Ordoñez, Tania Cid-Diaz, Qixiu Han, Angeles Duran, Yu Muta, Xiao Zhang, Juan F Linares, Yuki Nakanishi, Hiroaki Kasashima, Masakazu Yashiro, Kiyoshi Maeda, Ana Albaladejo-Gonzalez, Daniel Torres-Moreno, José García-Solano, Pablo Conesa-Zamora, Giorgio Inghirami, Maria T Diaz-Meco, Jorge Moscat.
      The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5+. This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin.
    Keywords:  AP-1; JNK; Yap; aPKC; cell death; colorectal cancer; intestinal stem cell; metaplasia; preneoplasia; tumor initiation
    DOI:  https://doi.org/10.1016/j.devcel.2024.05.001
  2. Nat Rev Gastroenterol Hepatol. 2024 May 28.
    Mechanisms of metastatic colorectal cancer.
    Adrià Cañellas-Socias, Elena Sancho, Eduard Batlle.
      Despite extensive research and improvements in understanding colorectal cancer (CRC), its metastatic form continues to pose a substantial challenge, primarily owing to limited therapeutic options and a poor prognosis. This Review addresses the emerging focus on metastatic CRC (mCRC), which has historically been under-studied compared with primary CRC despite its lethality. We delve into two crucial aspects: the molecular and cellular determinants facilitating CRC metastasis and the principles guiding the evolution of metastatic disease. Initially, we examine the genetic alterations integral to CRC metastasis, connecting them to clinically marked characteristics of advanced CRC. Subsequently, we scrutinize the role of cellular heterogeneity and plasticity in metastatic spread and therapy resistance. Finally, we explore how the tumour microenvironment influences metastatic disease, emphasizing the effect of stromal gene programmes and the immune context. The ongoing research in these fields holds immense importance, as its future implications are projected to revolutionize the treatment of patients with mCRC, hopefully offering a promising outlook for their survival.
    DOI:  https://doi.org/10.1038/s41575-024-00934-z
  3. STAR Protoc. 2024 May 28. pii: S2666-1667(24)00255-7. [Epub ahead of print]5(2): 103090
    Protocol for generation of and high-throughput drug testing with patient-derived colorectal cancer organoids.
    Tao Tan, Dmitri Mouradov, Peter Gibbs, Oliver M Sieber.
      Drug sensitivity testing of patient-derived tumor organoids (PDTOs) is a promising tool for personalizing cancer treatment. Here, we present a protocol for generation of and high-throughput drug testing with PDTOs. We describe detailed steps for PDTO establishment from colorectal cancer tissues, preparation of PDTOs for high-throughput drug testing, and quantification of drug testing results using image analysis. This protocol provides a standardized workflow for PDTO testing of standard-of-care therapies, along with exploring the activity of new agents, for translational research. For complete details on the use and execution of this protocol, please refer to Tan et al.1.
    Keywords:  cancer; cell culture; high throughput screening; microscopy; organoids
    DOI:  https://doi.org/10.1016/j.xpro.2024.103090
  4. J Cancer. 2024 ;15(11): 3441-3451
    5-Fluorouracil resistant CRC cells derived exosomes promote cancer-associated fibroblasts secreting more CXCL12.
    Tongxin Zhang, Zilong He, Xiaowei Qi, Yu Zhang, Yankui Liu, Linfang Jin, Teng Wang.
      Background: Chemoresistance is a key reason for treatment failure in colorectal cancer (CRC) patients. The tumor microenvironment of chemoresistant CRC is distinctly immunosuppressive, although the underlying mechanisms are unclear. Methods: The CRC data sets GSE69657 and GSE62080 were downloaded from the GEO database, and the correlation between TRPC5 and FAP expression was analyzed by Pearson method. The in-situ expression of transient receptor potential channel 5 (TRPC5) and fibroblast activation protein (FAP) in the CRC tissues was examined by immunohistochemistry. TRPC5 expression levels in the HCT8 and HCT116 cell lines and the corresponding 5-fluorouracil (5-FU)-resistant cell lines (HCT8R and HCT116R) were analyzed by western blotting and RT-PCR. Exosomes were isolated from the HCT8R and HCT116R cells and incubated with colorectal normal fibroblasts (NFs), and cancer-associated fibroblasts (CAFs)markers were detected. NFs were also incubated with exosomes isolated from TRPC5-knockdown HCT8R cells, and the changes in intracellular Ca2+ levels and C-X-C motif chemokine ligand 12 (CXCL12) secretion were analyzed. Results: TRPC5 and FAP expression showed positive correlation in the datasets. Immunostaining of CRC tissue specimens further revealed that high TRPC5 and FAP expressions were significantly associated with worse tumor regression. Furthermore, chemoresistant CRC cells expressed higher levels of TRPC5 compared to the chemosensitive cells, and knocking down TRPC5 reversed chemoresistance. Exosomes derived from CRC cells induced the transformation of NFs to CAFs. However, TRPC5-exosomes derived from chemoresistant CRC cells can promote CAFs to secrete more CXCL12. Conclusion: Chemoresistant CRC cells can induce CAFs activation and promote CXCL12 secretion through exosomal TRPC5.
    Keywords:  CXCL12; Cancer-associated fibroblast; Chemoresistance; Colorectal cancer; Transient receptor potential canonical 5
    DOI:  https://doi.org/10.7150/jca.95248
  5. Trends Cancer. 2024 May 30. pii: S2405-8033(24)00091-8. [Epub ahead of print]
    Advancements in combining targeted therapy and immunotherapy for colorectal cancer.
    Manisha Singh, Van Karlyle Morris, Irfan N Bandey, David S Hong, Scott Kopetz.
      Colorectal cancer (CRC) is a prevalent gastrointestinal cancer posing significant clinical challenges. CRC management traditionally involves surgery, often coupled with chemotherapy. However, unresectable or metastatic CRC (mCRC) presents a complex challenge necessitating innovative treatment strategies. Targeted therapies have emerged as the cornerstone of treatment in such cases, with interventions tailored to specific molecular attributes. Concurrently, immunotherapies have revolutionized cancer treatment by harnessing the immune system to combat malignant cells. This review explores the evolving landscape of CRC treatment, focusing on the synergy between immunotherapies and targeted therapies, thereby offering new avenues for enhancing the effectiveness of therapy for CRC.
    Keywords:  colorectal cancer (CRC); immune checkpoint inhibitors; immunotherapies; targeted therapies
    DOI:  https://doi.org/10.1016/j.trecan.2024.05.001
  6. Science. 2024 May 31. 384(6699): eadi7453
    Stem-cell states converge in multistage cutaneous squamous cell carcinoma development.
    Mark A Taylor, Eve Kandyba, Kyle Halliwill, Reyno Delrosario, Matvei Khoroshkin, Hani Goodarzi, David Quigley, Yun Rose Li, Di Wu, Saumya R Bollam, Olga K Mirzoeva, Rosemary J Akhurst, Allan Balmain.
      Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse tissue samples (both normal and tumor) and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in premalignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship. Treatment of carcinomas in vivo with chemotherapy repressed the proliferative state and activated multilineage plasticity whereas inhibition of differentiation repressed plasticity and potentiated responses to cell cycle inhibitors. Manipulation of this cell state transition point may provide a source of potential combinatorial targets for cancer therapy.
    DOI:  https://doi.org/10.1126/science.adi7453
  7. Adv Exp Med Biol. 2024 May 30.
    The Potential Role of Intestinal Stem Cells and Microbiota for the Treatment of Colorectal Cancer.
    Babak Arjmand, Sepideh Alavi-Moghadam, Zahra Faraji, Morteza Aghajanpoor-Pasha, Hasan Jalaeikhoo, Mohsen Rajaeinejad, Mohsen Nikandish, Ali Faridfar, Ahmad Rezazadeh-Mafi, Mostafa Rezaei-Tavirani, Arsalan Irompour.
      Colorectal cancer is a global health concern with high incidence and mortality rates. Conventional treatments like surgery, chemotherapy, and radiation therapy have limitations in improving patient survival rates. Recent research highlights the role of gut microbiota and intestinal stem cells in maintaining intestinal health and their potential therapeutic applications in colorectal cancer treatment. The interaction between gut microbiota and stem cells influences epithelial self-renewal and overall intestinal homeostasis. Novel therapeutic approaches, including immunotherapy, targeted therapy, regenerative medicine using stem cells, and modulation of gut microbiota, are being explored to improve treatment outcomes. Accordingly, this chapter provides an overview of the potential therapeutic applications of gut microbiota and intestinal stem cells in treating colorectal cancer.
    Keywords:  Cell therapy; Colorectal cancer; Gastrointestinal tract; Gut microbiota; Intestinal stem cells; Regenerative medicine
    DOI:  https://doi.org/10.1007/5584_2024_803
  8. Sci Signal. 2024 May 28. 17(838): eadp3504
    A connection between phosphatidylinositol 5-phosphate and the Hippo pathway to prevent epithelial-mesenchymal transition in cancer.
    Emilio Hirsch, Emanuele Fantastico, Lorenzo Prever, Federico Gulluni.
      The Hippo pathway blocks epithelial-mesenchymal transition and metastasis in cancer mediated by the transcriptional coactivator YAP. In this issue of Science Signaling, Palamiuc et al. demonstrate that phosphatidylinositol 5-phosphate (PI5P) enhances Hippo pathway activation and that simultaneously the Hippo pathway initiates a positive feedback loop by inhibiting the conversion of PI5P into PIP2.
    DOI:  https://doi.org/10.1126/scisignal.adp3504
  9. iScience. 2024 Jun 21. 27(6): 109909
    Pro-inflammatory T cells-derived cytokines enhance the maturation of the human fetal intestinal epithelial barrier.
    Francesca P Giugliano, Marit Navis, Sarah Ouahoud, Tânia Martins Garcia, Irini A M Kreulen, Evelina Ferrantelli, Sander Meisner, Jacqueline L M Vermeulen, Manon van Roest, Jean-Noël Billaud, Jan Koster, Yousif Dawood, Bernadette S de Bakker, Daisy I Picavet-Havik, Irene M Schimmel, Nicole N van der Wel, Pim J Koelink, Manon E Wildenberg, Joep P M Derikx, Wouter J de Jonge, Ingrid B Renes, Ruurd M van Elburg, Vanesa Muncan.
      Small intestine (SI) maturation during early life is pivotal in preventing the onset of gut diseases. In this study we interrogated the milestones of SI development by gene expression profiling and ingenuity pathway analyses. We identified a set of cytokines as main regulators of changes observed across different developmental stages. Upon cytokines stimulation, with IFNγ as the most contributing factor, human fetal organoids (HFOs) increase brush border gene expression and enzyme activity as well as trans-epithelial electrical resistance. Electron microscopy revealed developed brush border and loss of fetal cell characteristics in HFOs upon cytokine stimulation. We identified T cells as major source of IFNγ production in the fetal SI lamina propria. Co-culture of HFOs with T cells recapitulated the major effects of cytokine stimulation. Our findings underline pro-inflammatory cytokines derived from T cells as pivotal factors inducing functional SI maturation in vivo and capable of modulating the barrier maturation of HFOs in vitro.
    Keywords:  Cell biology; Developmental biology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2024.109909
  10. Sci Rep. 2024 05 30. 14(1): 12477
    TCF7L1 regulates colorectal cancer cell migration by repressing GAS1 expression.
    Carli M King, Wei Ding, Melanie A Eshelman, Gregory S Yochum.
      Dysregulated Wnt/β-catenin signaling is a common feature of colorectal cancer (CRC). The T-cell factor/lymphoid enhancer factor (TCF/LEF; hereafter, TCF) family of transcription factors are critical regulators of Wnt/β-catenin target gene expression. Of the four TCF family members, TCF7L1 predominantly functions as a transcriptional repressor. Although TCF7L1 has been ascribed an oncogenic role in CRC, only a few target genes whose expression it regulates have been characterized in this cancer. Through transcriptome analyses of TCF7L1 regulated genes, we noted enrichment for those associated with cellular migration. By silencing and overexpressing TCF7L1 in CRC cell lines, we demonstrated that TCF7L1 promoted migration, invasion, and adhesion. We localized TCF7L1 binding across the CRC genome and overlapped enriched regions with transcriptome data to identify candidate target genes. The growth arrest-specific 1 (GAS1) gene was among these and we demonstrated that GAS1 is a critical mediator of TCF7L1-dependent CRC cell migratory phenotypes. Together, these findings uncover a novel role for TCF7L1 in repressing GAS1 expression to enhance migration and invasion of CRC cells.
    DOI:  https://doi.org/10.1038/s41598-024-63346-8
  11. Nat Rev Cancer. 2024 May 29.
    No mutation, tumour initiation.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-024-00711-9
  12. J Transl Med. 2024 May 27. 22(1): 509
    Identification of epigenetic silencing of the SFRP2 gene in colorectal cancer as a clinical biomarker and molecular significance.
    Hatim Boughanem, Jesús Pilo, Libia Alejandra García-Flores, Isabel Arranz, María Ramos-Fernandez, María Ortega-Castan, Ana B Crujeiras, Juan Sandoval, Manuel Macias-Gonzalez.
       BACKGROUND: Several studies have suggested secreted frizzled-related protein 2 (SFRP2) gene as a potential clinical biomarker in colorectal cancer (CRC). However, its diagnostic role remains unclear. In this study, we aimed to investigate the significance of SFRP2 methylation levels in a large cohort of biological specimens (including blood, adipose and colonic tissues) from patients with CRC, thereby potentially identifying new biomarker utility.
    METHODS: We examined the expression (by qPCR) and methylation status (by 450 K DNA array and DNA pyrosequencing) of the SFRP2 gene in healthy participants (N = 110, aged as 53.7 (14.2), 48/62 males/females) and patients with CRC (N = 85, aged 67.7 (10.5), 61/24 males/females), across different biological tissues, and assessing its potential as a biomarker for CRC. Additionally, we investigated the effect of recombinant human SFRP2 (rhSFRP2) as a therapeutic target, on cell proliferation, migration, and the expression of key genes related to carcinogenesis and the Wnt pathway.
    RESULTS: Our findings revealed that SFRP2 promoter methylation in whole blood could predict cancer stage (I + II vs. III + IV) (AUC = 0.653), lymph node invasion (AUC = 0.692), and CRC recurrence (AUC = 0.699) in patients with CRC (all with p < 0.05). Furthermore, we observed a global hypomethylation of SFRP2 in tumors compared to the adjacent area (p < 0.001). This observation was validated in the TCGA-COAD and TCGA-READ cohorts, demonstrating overall hypermethylation (both with p < 0.001) and low expression (p < 0.001), as shown in publicly available scRNA-Seq data. Notably, neoadjuvant-treated CRC patients exhibited lower SFRP2 methylation levels compared to untreated patients (p < 0.05) and low promoter SFRP2 methylation in untreated patients was associated with poor overall survival (p < 0.05), when compared to high methylation. Finally, treatment with 5 µg of rhSFRP2 treatment in CRC cells (HCT116 cells) inhibited cell proliferation (p < 0.001) and migration (p < 0.05), and downregulated the expression of AXIN2 (p < 0.01), a gene involved in Wnt signaling pathway.
    CONCLUSIONS: These findings establish promoter methylation of the SFRP2 gene as a prognostic candidate in CRC when assessed in blood, and as a therapeutic prognostic candidate in tumors, potentially valuable in clinical practice. SFRP2 also emerges as a therapeutic option, providing new clinical and therapeutical avenues.
    Keywords:   SRFP2 ; Colorectal cancer biomarkers; DNA methylation; Promoter methylation; Wnt signaling pathway
    DOI:  https://doi.org/10.1186/s12967-024-05329-x
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