bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2021–12–05
eleven papers selected by
Maria-Virginia Giolito, IRFAC/UMR-S1113 INSERM
  1. Adipose stromal cells promote the transition of colorectal cancer cells toward a mesenchymal-like phenotype.
  2. Thymidylate synthase O-GlcNAcylation: a molecular mechanism of 5-FU sensitization in colorectal cancer.
  3. Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR.
  4. RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine.
  5. Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma in murine model.
  6. Redox-sensitive cyclophilin A elicits chemoresistance through realigning cellular oxidative status in colorectal cancer.
  7. Regulatory role of the transforming growth factor-β signaling pathway in the drug resistance of gastrointestinal cancers.
  8. Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα.
  9. Identification of liver-derived bone morphogenetic protein (BMP)-9 as a potential new candidate for treatment of colorectal cancer.
  10. Hypoxia as a driver of resistance to immunotherapy.
  11. A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer.
  1. Mol Cell Oncol. 2021 ;8(5): 1986343
    Adipose stromal cells promote the transition of colorectal cancer cells toward a mesenchymal-like phenotype.
    Simone Di Franco, Giorgio Stassi.
      Colon cancer progression is among the risks that increase with obesity. We have recently unveiled the molecular mechanism by which adipose tissue-released molecules, HGF and IL-6, make colorectal cancer (CRC) cells acquiring mesenchymal traits. Targeting of adipose-derived factors abrogate the metastatic potential of CRC stem cells (CR-CSCs) in obese patients.
    DOI:  https://doi.org/10.1080/23723556.2021.1986343
  2. Oncogene. 2021 Nov 29.
    Thymidylate synthase O-GlcNAcylation: a molecular mechanism of 5-FU sensitization in colorectal cancer.
    Ninon Very, Stéphan Hardivillé, Amélie Decourcelle, Julien Thévenet, Madjid Djouina, Adeline Page, Gérard Vergoten, Céline Schulz, Julie Kerr-Conte, Tony Lefebvre, Vanessa Dehennaut, Ikram El Yazidi-Belkoura.
      Alteration of O-GlcNAcylation, a dynamic posttranslational modification, is associated with tumorigenesis and tumor progression. Its role in chemotherapy response is poorly investigated. Standard treatment for colorectal cancer (CRC), 5-fluorouracil (5-FU), mainly targets Thymidylate Synthase (TS). TS O-GlcNAcylation was reported but not investigated yet. We hypothesize that O-GlcNAcylation interferes with 5-FU CRC sensitivity by regulating TS. In vivo, we observed that combined 5-FU with Thiamet-G (O-GlcNAcase (OGA) inhibitor) treatment had a synergistic inhibitory effect on grade and tumor progression. 5-FU decreased O-GlcNAcylation and, reciprocally, elevation of O-GlcNAcylation was associated with TS increase. In vitro in non-cancerous and cancerous colon cells, we showed that 5-FU impacts O-GlcNAcylation by decreasing O-GlcNAc Transferase (OGT) expression both at mRNA and protein levels. Reciprocally, OGT knockdown decreased 5-FU-induced cancer cell apoptosis by reducing TS protein level and activity. Mass spectrometry, mutagenesis and structural studies mapped O-GlcNAcylated sites on T251 and T306 residues and deciphered their role in TS proteasomal degradation. We reveal a crosstalk between O-GlcNAcylation and 5-FU metabolism in vitro and in vivo that converges to 5-FU CRC sensitization by stabilizing TS. Overall, our data propose that combining 5-FU-based chemotherapy with Thiamet-G could be a new way to enhance CRC response to 5-FU.
    DOI:  https://doi.org/10.1038/s41388-021-02121-9
  3. PLoS Genet. 2021 Nov 29. 17(11): e1009931
    Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR.
    Carolina Mantilla Rojas, Michael P McGill, Anna C Salvador, David Bautz, David W Threadgill.
      ERBB3 has gained attention as a potential therapeutic target to treat colorectal and other types of cancers. To confirm a previous study showing intestinal polyps are dependent upon ERBB3, we generated an intestinal epithelia-specific ERBB3 deletion in C57BL/6-ApcMin/+ mice. Contrary to the previous report showing a significant reduction in intestinal polyps with ablation of ERBB3 on a B6;129 mixed genetic background, we observed a significant increase in polyp number with ablation of ERBB3 on C57BL/6J compared to control littermates. We confirmed the genetic background dependency of ERBB3 by also analyzing polyp development on B6129 hybrid and B6;129 advanced intercross mixed genetic backgrounds, which showed that ERBB3 deficiency only reduced polyp number on the mixed background as previously reported. Increased polyp number with ablation of ERBB3 was also observed in C57BL/6J mice treated with azoxymethane showing the effect is model independent. Polyps forming in absence of ERBB3 were generally smaller than those forming in control mice, albeit the effect was greatest in genetic backgrounds with reduced polyp numbers. The mechanism for differential polyp number in the absence of ERBB3 was through altered proliferation. Backgrounds with increased polyp number with loss of ERBB3 showed an increase in cell proliferation even in non-tumor epithelia, while backgrounds showing reduced polyp number with loss of ERBB3 showed reduced cellular proliferation. Increase polyp number caused by loss of ERBB3 was mediated by increased epidermal growth factor receptor (EGFR) expression, which was confirmed by deletion of Egfr. Taken together, this study raises substantial implications on the use of ERBB3 inhibitors against colorectal cancer. The prediction is that some patients may have increased progression with ERBB3 inhibitor therapy, which is consistent with observations reported for ERBB3 inhibitor clinical trials.
    DOI:  https://doi.org/10.1371/journal.pgen.1009931
  4. Gut. 2021 Dec 01. pii: gutjnl-2021-324984. [Epub ahead of print]
    RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine.
    Tianyun Long, Nazia Abbasi, Juan E Hernandez, Yuxin Li, Ibrahim M Sayed, Shengyun Ma, Attilio Iemolo, Brian A Yee, Gene W Yeo, Francesca Telese, Pradipta Ghosh, Soumita Das, Wendy Jia Men Huang.
       OBJECTIVE: Tuft cells residing in the intestinal epithelium have diverse functions. In the small intestine, they provide protection against inflammation, combat against helminth and protist infections, and serve as entry portals for enteroviruses. In the colon, they had been implicated in tumourigenesis. Commitment of intestinal progenitor cells to the tuft cell lineage requires Rho GTPase Cell Division Cycle 42 (CDC42), a Rho GTPase that acts downstream of the epidermal growth factor receptor and wingless-related integration site signalling cascades, and the master transcription factor POU class 2 homeobox 3 (POU2F3). This study investigates how this pathway is regulated by the DEAD box containing RNA binding protein DDX5 in vivo.
    DESIGN: We assessed the role of DDX5 in tuft cell specification and function in control and epithelial cell-specific Ddx5 knockout mice (DDX5ΔIEC) using transcriptomic approaches.
    RESULTS: DDX5ΔIEC mice harboured a loss of intestinal tuft cell populations, modified microbial repertoire, and altered susceptibilities to ileal inflammation and colonic tumourigenesis. Mechanistically, DDX5 promotes CDC42 protein synthesis through a post-transcriptional mechanism to license tuft cell specification. Importantly, the DDX5-CDC42 axis is parallel but distinct from the known interleukin-13 circuit implicated in tuft cell hyperplasia, and both pathways augment Pou2f3 expression in secretory lineage progenitors. In mature tuft cells, DDX5 not only promotes integrin signalling and microbial responses, it also represses gene programmes involved in membrane transport and lipid metabolism.
    CONCLUSION: RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine.
    Keywords:  colon carcinogenesis; epithelial differentiation; gut inflammation; small intestine
    DOI:  https://doi.org/10.1136/gutjnl-2021-324984
  5. iScience. 2021 Dec 17. 24(12): 103369
    Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma in murine model.
    Bahar Degirmenci, Cansu Dincer, Habibe Cansu Demirel, Linda Berkova, Andreas E Moor, Abdullah Kahraman, George Hausmann, Michel Aguet, Nurcan Tuncbag, Tomas Valenta, Konrad Basler.
      Colon cancer is initiated by stem cells that escape the strict control. This process is often driven through aberrant activation of Wnt signaling by mutations in components acting downstream of the receptor complex that unfetter tumor cells from the need for Wnts. Here we describe a class of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells autosecrete Wnts to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt-dependent colon cancer that might be responsive to Wnt secretion inhibitors.
    Keywords:  Cancer; Cell biology; Immunology; Molecular physiology; Omics
    DOI:  https://doi.org/10.1016/j.isci.2021.103369
  6. Cell Rep. 2021 Nov 30. pii: S2211-1247(21)01555-2. [Epub ahead of print]37(9): 110069
    Redox-sensitive cyclophilin A elicits chemoresistance through realigning cellular oxidative status in colorectal cancer.
    Liyuan Peng, Jingwen Jiang, Hai-Ning Chen, Li Zhou, Zhao Huang, Siyuan Qin, Ping Jin, Maochao Luo, Bowen Li, Jiayan Shi, Na Xie, Lih-Wen Deng, Yih-Cherng Liou, Edouard C Nice, Canhua Huang, Yuquan Wei.
      Cancer cells utilize rapidly elevated cellular antioxidant programs to accommodate chemotherapy-induced oxidative stress; however, the underlying mechanism remains largely unexplored. Here we screen redox-sensitive effectors as potential therapeutic targets for colorectal cancer (CRC) treatment and find that cyclophilin A (CypA) is a compelling candidate. Our results show that CypA forms an intramolecular disulfide bond between Cys115 and Cys161 upon oxidative stress and the oxidized cysteines in CypA are recycled to a reduced state by peroxiredoxin-2 (PRDX2). Furthermore, CypA reduces cellular reactive oxygen species levels and increases CRC cell survival under insults of H2O2 and chemotherapeutics through a CypA-PRDX2-mediated antioxidant apparatus. Notably, CypA is upregulated in chemoresistant CRC samples, which predicts poor prognosis. Moreover, targeting CypA by cyclosporine A exhibits promising efficacy against chemoresistant CRC when combined with chemotherapeutics. Collectively, our findings highlight CypA as a component of cellular noncanonical antioxidant defense and as a potential druggable therapeutic target to ameliorate CRC chemoresistance.
    Keywords:  CRC; CypA; PRDX2; ROS; antioxidant system; colorectal cancer; disulfide bond; drug resistance; oxidative stress; reactive oxygen species; redox modification; redox signaling
    DOI:  https://doi.org/10.1016/j.celrep.2021.110069
  7. World J Gastrointest Oncol. 2021 Nov 15. 13(11): 1648-1667
    Regulatory role of the transforming growth factor-β signaling pathway in the drug resistance of gastrointestinal cancers.
    Xiaoqun Lv, Guoxiong Xu.
      Gastrointestinal (GI) cancer, including esophageal, gastric, and colorectal cancer, is one of the most prevalent types of malignant carcinoma and the leading cause of cancer-related deaths. Despite significant advances in therapeutic strategies for GI cancers in recent decades, drug resistance with various mechanisms remains the prevailing cause of therapy failure in GI cancers. Accumulating evidence has demonstrated that the transforming growth factor (TGF)-β signaling pathway has crucial, complex roles in many cellular functions related to drug resistance. This review summarizes current knowledge regarding the role of the TGF-β signaling pathway in the resistance of GI cancers to conventional chemotherapy, targeted therapy, immunotherapy, and traditional medicine. Various processes, including epithelial-mesenchymal transition, cancer stem cell development, tumor microenvironment alteration, and microRNA biogenesis, are proposed as the main mechanisms of TGF-β-mediated drug resistance in GI cancers. Several studies have already indicated the benefit of combining antitumor drugs with agents that suppress the TGF-β signaling pathway, but this approach needs to be verified in additional clinical studies. Moreover, the identification of potential biological markers that can be used to predict the response to TGF-β signaling pathway inhibitors during anticancer treatments will have important clinical implications in the future.
    Keywords:  Cancer stem cells; Drug resistance; Epithelial-mesenchymal transition; Gastrointestinal cancer; MicroRNAs; Transforming growth factor-β
    DOI:  https://doi.org/10.4251/wjgo.v13.i11.1648
  8. Nat Commun. 2021 Dec 02. 12(1): 7031
    Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα.
    Ozren Stojanović, Jordi Altirriba, Dorothée Rigo, Martina Spiljar, Emilien Evrard, Benedek Roska, Salvatore Fabbiano, Nicola Zamboni, Pierre Maechler, Françoise Rohner-Jeanrenaud, Mirko Trajkovski.
      Intestinal surface changes in size and function, but what propels these alterations and what are their metabolic consequences is unknown. Here we report that the food amount is a positive determinant of the gut surface area contributing to an increased absorptive function, reversible by reducing daily food. While several upregulated intestinal energetic pathways are dispensable, the intestinal PPARα is instead necessary for the genetic and environment overeating-induced increase of the gut absorptive capacity. In presence of dietary lipids, intestinal PPARα knock-out or its pharmacological antagonism suppress intestinal crypt expansion and shorten villi in mice and in human intestinal biopsies, diminishing the postprandial triglyceride transport and nutrient uptake. Intestinal PPARα ablation limits systemic lipid absorption and restricts lipid droplet expansion and PLIN2 levels, critical for droplet formation. This improves the lipid metabolism, and reduces body adiposity and liver steatosis, suggesting an alternative target for treating obesity.
    DOI:  https://doi.org/10.1038/s41467-021-27133-7
  9. J Cell Mol Med. 2021 Nov 28.
    Identification of liver-derived bone morphogenetic protein (BMP)-9 as a potential new candidate for treatment of colorectal cancer.
    Chen Cai, Timo Itzel, Haristi Gaitantzi, Carolina de la Torre, Emrullah Birgin, Johannes Betge, Norbert Gretz, Andreas Teufel, Nuh N Rahbari, Matthias P Ebert, Katja Breitkopf-Heinlein.
      Colorectal cancer (CRC) is a high-incidence malignancy worldwide which still needs better therapy options. Therefore, the aim of the present study was to investigate the responses of normal or malignant human intestinal epithelium to bone morphogenetic protein (BMP)-9 and to find out whether the application of BMP-9 to patients with CRC or the enhancement of its synthesis in the liver could be useful strategies for new therapy approaches. In silico analyses of CRC patient cohorts (TCGA database) revealed that high expression of the BMP-target gene ID1, especially in combination with low expression of the BMP-inhibitor noggin, is significantly associated with better patient survival. Organoid lines were generated from human biopsies of colon cancer (T-Orgs) and corresponding non-malignant areas (N-Orgs) of three patients. The N-Orgs represented tumours belonging to three different consensus molecular subtypes (CMS) of CRC. Overall, BMP-9 stimulation of organoids promoted an enrichment of tumour-suppressive gene expression signatures, whereas the stimulation with noggin had the opposite effects. Furthermore, treatment of organoids with BMP-9 induced ID1 expression (independently of high noggin levels), while treatment with noggin reduced ID1. In summary, our data identify the ratio between ID1 and noggin as a new prognostic value for CRC patient outcome. We further show that by inducing ID1, BMP-9 enhances this ratio, even in the presence of noggin. Thus, BMP-9 is identified as a novel target for the development of improved anti-cancer therapies of patients with CRC.
    Keywords:  ID1; bone morphogenetic protein-9; colorectal cancer; noggin
    DOI:  https://doi.org/10.1111/jcmm.17084
  10. Drug Resist Updat. 2021 Nov 18. pii: S1368-7646(21)00045-5. [Epub ahead of print] 100787
    Hypoxia as a driver of resistance to immunotherapy.
    Joanna Kopecka, Iris C Salaroglio, Elizabeth Perez-Ruiz, Ana Bela Sarmento-Ribeiro, Simona Saponara, Javier De Las Rivas, Chiara Riganti.
      Hypoxia, a hallmark of solid tumors, determines the selection of invasive and aggressive malignant clones displaying resistance to radiotherapy, conventional chemotherapy or targeted therapy. The recent introduction of immunotherapy, based on immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cells, has markedly transformed the prognosis in some tumors but also revealed the existence of intrinsic or acquired drug resistance. In the current review we highlight hypoxia as a culprit of immunotherapy failure. Indeed, multiple metabolic cross talks between tumor and stromal cells determine the prevalence of immunosuppressive populations within the hypoxic tumor microenvironment and confer upon tumor cells resistance to ICPIs and CAR T-cells. Notably, hypoxia-triggered angiogenesis causes immunosuppression, adding another piece to the puzzle of hypoxia-induced immunoresistance. If these factors concurrently contribute to the resistance to immunotherapy, they also unveil an unexpected Achille's heel of hypoxic tumors, providing the basis for innovative combination therapies that may rescue the efficacy of ICPIs and CAR T-cells. Although these treatments reveal both a bright side and a dark side in terms of efficacy and safety in clinical trials, they represent the future solution to enhance the efficacy of immunotherapy against hypoxic and therapy-resistant solid tumors.
    Keywords:  CAR T-cells; Drug resistance; Immune checkpoint inhibitors; Tumor hypoxia
    DOI:  https://doi.org/10.1016/j.drup.2021.100787
  11. Front Oncol. 2021 ;11 737323
    A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer.
    Maolin Wang, Xing-Sheng Shu, Meiqi Li, Yilin Zhang, Youli Yao, Xiaoyan Huang, Jianna Li, Pengfei Wei, Zhendan He, Jun Lu, Ying Ying.
       Background: Modifying the structure of anti-tumor chemotherapy drug is of significance to enhance the specificity and efficacy of drug-delivery. A novel proteolysis resistant PD-L1-targeted peptide (PPA1) has been reported to bind to PD-L1 and disrupt the PD-1/PD-L1 interaction, thus appearing as an outstanding tumor-targeting modification of synergistic drug conjugate for effective anti-tumor treatment. However, the combination regimen of coupling PD-L1 polypeptide with chemotherapeutic drug in tumoricidal treatment has not been reported thus far.
    Methods: We developed a novel synergistic strategy by conjugating PPA1 to doxorubicin (DOX) with a pH sensitive linker that can trigger the release of DOX near acidic tumor tissues. The binding affinity of PPA1-DOX with PD-L1 and the acid-sensitive cleavage of PPA1-DOX were investigated. A mouse xenograft model of colon cancer was used to evaluate the biodistribution, cytotoxicity and anti-tumor activity of PPA1-DOX.
    Results: PPA1-DOX construct showed high binding affinity with PD-L1 in vitro and specifically enriched within tumor when administered in vivo. PPA1-DOX exhibited a significantly lower toxicity and a remarkably higher antitumor activity in vivo, as compared with free PPA1, random polypeptide-DOX conjugate, DOX, or 5-FU, respectively. Moreover, increased infiltration of both CD4+ and CD8+ T cells was found in tumors from PPA1-DOX treated mice.
    Conclusions: We describe here for the first time that the dual-functional conjugate PPA1-DOX, which consist of the PD-L1-targeted polypeptide that renders both the tumor-specific drug delivery and inhibitory PD-1/PD-L1 immune checkpoint inhibition, and a cytotoxic agent that is released and kills tumor cells once reaching tumor tissues, thus representing a promising therapeutic option for colon cancer with improved efficacy and reduced toxicity.
    Keywords:  PD-L1 targeting polypeptide; chemotherapeutics drug release; colon cancer; pH sensitive linker; target delivery system
    DOI:  https://doi.org/10.3389/fonc.2021.737323
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