bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023‒10‒15
seven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Metabolic interventions to enhance immunotherapy and targeted therapy efficacy in advanced colorectal cancer.
  2. Metabolic support by macrophages sustains colonic epithelial homeostasis.
  3. TRIP6 disrupts tight junctions to promote metastasis and drug resistance and is a therapeutic target in colorectal cancer.
  4. Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.
  5. Rigosertib promotes anti-tumor immunity via autophagic degradation of PD-L1 in colorectal cancer cells.
  6. Stearoyl-CoA desaturase 1 inhibition impairs triacylglycerol accumulation and lipid droplet formation in colorectal cancer cells.
  7. Identification of ATF3 as a novel protective signature of quiescent colorectal tumor cells.
  1. Curr Opin Chem Biol. 2023 Oct 06. pii: S1367-5931(23)00139-4. [Epub ahead of print]77 102401
    Metabolic interventions to enhance immunotherapy and targeted therapy efficacy in advanced colorectal cancer.
    Helena Oliveres, Marta Cascante, Joan Maurel.
      Current standard-of-care for metastatic colorectal cancer patients includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor for microsatellite stable tumors and pembrolizumab for microsatellite instable tumors. However, despite the available therapies, the prognosis remains poor. In recent years, new drugs combined with immune checkpoint inhibitors have been tested in microsatellite stable metastatic colorectal cancer patients, but the benefit was modest. Here, we review the metabolic interactions between the immune microenvironment and cancer cells. More specifically, we highlight potential correlatives of tumor immune and metabolic features with transcriptomic classifications such as the Consensus Molecular Subtype. Finally, we discuss the unmet need of immune-metabolic signatures and the value of a new signature (IMMETCOLS) for guiding new strategies in metastatic colorectal cancer. We conclude that the field is ready to propose customized strategies for modifying metabolism and improving immunotherapy and targeted therapy efficacy.
    Keywords:  Immunotherapy; Metabolism; Resistance
    DOI:  https://doi.org/10.1016/j.cbpa.2023.102401
  2. Cell Metab. 2023 Sep 29. pii: S1550-4131(23)00341-8. [Epub ahead of print]
    Metabolic support by macrophages sustains colonic epithelial homeostasis.
    Stephanie Deborah Fritsch, Nyamdelger Sukhbaatar, Karine Gonzales, Alishan Sahu, Loan Tran, Andrea Vogel, Mario Mazic, Jayne Louise Wilson, Stephan Forisch, Hannah Mayr, Raimund Oberle, Jakob Weiszmann, Martin Brenner, Roeland Vanhoutte, Melanie Hofmann, Sini Pirnes-Karhu, Christoph Magnes, Torben Kühnast, Wolfram Weckwerth, Christoph Bock, Kristaps Klavins, Markus Hengstschläger, Christine Moissl-Eichinger, Gernot Schabbauer, Gerda Egger, Eija Pirinen, Steven H L Verhelst, Thomas Weichhart.
      The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently characterized signals from the microenvironment. Here, we showed that colonic macrophages were located directly adjacent to epithelial crypt cells in mice, where they metabolically supported epithelial cell proliferation in an mTORC1-dependent manner. Specifically, deletion of tuberous sclerosis complex 2 (Tsc2) in macrophages activated mTORC1 signaling that protected against colitis-induced intestinal damage and induced the synthesis of the polyamines spermidine and spermine. Epithelial cells ingested these polyamines and rewired their cellular metabolism to optimize proliferation and defense. Notably, spermine directly stimulated proliferation of colon epithelial cells and colon organoids. Genetic interference with polyamine production in macrophages altered global polyamine levels in the colon and modified epithelial cell proliferation. Our results suggest that macrophages act as "commensals" that provide metabolic support to promote efficient self-renewal of the colon epithelium.
    Keywords:  arginase-1; homeostasis; immunometabolism; intestine; mTOR; mTORC1; macrophages; polyamines; spermine
    DOI:  https://doi.org/10.1016/j.cmet.2023.09.010
  3. Cancer Lett. 2023 Oct 10. pii: S0304-3835(23)00389-0. [Epub ahead of print] 216438
    TRIP6 disrupts tight junctions to promote metastasis and drug resistance and is a therapeutic target in colorectal cancer.
    Hongyan Gou, Chi Chun Wong, Huarong Chen, Haiyun Shang, Hao Su, Jianning Zhai, Weixin Liu, Wenxiu Liu, Donglei Sun, Xin Wang, Jun Yu.
      Metastasis is the primary cause of death in colorectal cancer (CRC). Thyroid hormone receptor interacting protein 6 (TRIP6) is an adaptor protein that regulates cell motility. Here, we aim to elucidate the role of TRIP6 in driving CRC tumorigenesis and metastasis and evaluate its potential as a therapeutic target. TRIP6 mRNA is up-regulated in CRC compared to adjacent normal tissues in three independent cohorts (all P < 0.0001), especially in liver metastases (P < 0.01). High TRIP6 expression predicts poor prognosis of CRC patients in our cohort (P = 0.01) and TCGA cohort (P < 0.01). Colon-specific TRIP6 overexpression (Trip6KIVillin-Cre) in mice accelerated azoxymethane (AOM)-induced CRC (P < 0.01) and submucosal invasion (P < 0.01). In contrast, TRIP6 knockout (Trip6+/- mice) slowed tumorigenesis (P < 0.01). Consistently, TRIP6 overexpression in CRC cells promoted epithelial-mesenchymal transition (EMT), cell migration/invasion in vitro, and metastases in vivo (all P < 0.01), whereas knockdown of TRIP6 exerted opposite phenotypes. Mechanistically, TRIP6 interacted PDZ domain-containing proteins such as PARD3 to impair tight junctions, evidenced by decreased tight junction markers and gut permeability dysfunction, inhibit PTEN, and activate oncogenic Akt signaling. TRIP6-induced pro-metastatic phenotypes and Akt activation depends on PARD3. Targeting TRIP6 by VNP-encapsulated TRIP6-siRNA synergized with Oxaliplatin and 5-Fluorouracil to suppress CRC liver metastases in mice. In conclusion, TRIP6 promotes CRC metastasis by directly interacting with PARD3 to disrupt tight junctions and activating Akt signaling. Targeting of TRIP6 in combination with chemotherapy is a promising strategy for the treatment of metastatic CRC.
    Keywords:  Chemotherapy; Colorectal cancer; Epithelial-mesenchymal transition; TRIP6; Tight junction
    DOI:  https://doi.org/10.1016/j.canlet.2023.216438
  4. Cell Death Dis. 2023 Oct 10. 14(10): 664
    Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.
    Sumati Hasani, Lyndsay E A Young, Warren Van Nort, Moumita Banerjee, Dylan R Rivas, Jinhwan Kim, Xiaopeng Xiong, Ramon C Sun, Matthew S Gentry, Hiromi Sesaki, Tianyan Gao.
      Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA and promote glycogen storage. Using 3D organoids from Apcf/f/Villin-CreERT2 models, we show that glycogen levels are elevated in tumor organoids upon genetic deletion of Drp1. Similarly, increased GYS1 expression and glycogen accumulation are detected in xenograft tumors derived from Drp1 knockdown colon cancer cells. Functionally, increased glycogen storage provides survival advantage to Drp1 knockdown cells. Co-targeting glycogen phosphorylase-mediated glycogenolysis sensitizes Drp1 knockdown cells to chemotherapy drug treatment. Taken together, our results suggest that Drp1-loss activates glucose uptake and glycogenesis as compensative metabolic pathways to promote cell survival. Combined inhibition of glycogen metabolism may enhance the efficacy of chemotherapeutic agents for colon cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-023-06202-3
  5. Cancer Lett. 2023 Oct 05. pii: S0304-3835(23)00373-7. [Epub ahead of print]577 216422
    Rigosertib promotes anti-tumor immunity via autophagic degradation of PD-L1 in colorectal cancer cells.
    Xinyi Zhou, Dongliang Fu, Hang Yang, Chenqin Le, Yier Lu, Jingsun Wei, Yang Tang, Jiawei Zhang, Ying Yuan, Kefeng Ding, Qian Xiao.
      Rigosertib (RGS) is a benzyl styryl sulfone which exhibits impressive cytotoxicity in cancer cells. However, its modulating effect on tumor immune microenvironment remains elusive. In our experiments, compared with immunodeficient mouse model, increased tumor growth arrest and robust anti-tumor immunity were observed in RGS-treated colorectal cancer (CRC) isograft tumors in immunocompetent mice. Intriguingly, RGS markedly down-regulated programmed cell death ligand 1 (PD-L1) expression in both vivo and in vitro. Meanwhile, RGS increased autophagic vacuole number in CRC cells as seen by transmission electron microscopy and immunofluorescence. Moreover, increased LC3-II level and tandem-mRFP- GFP- LC3 labeled vacuole accumulation demonstrated RGS-induced autophagic flux. Mechanistically, it is the activation of AMP-activated protein kinase-UNC-51-like kinase 1 (AMPK-ULK1) axis, rather than the canonical mTOR signaling pathway, that plays a pivotal role in RGS-induced autophagy. AMPK-ULK1 dependent autophagy inhibition, by either short interfering RNA or chemical inhibitors, blocked RGS-induced PD-L1 degradation. Finally, RGS exhibited synergistic anti-tumor activity with cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody in the CRC isograft model. Furthermore, apart from the immunomodulatory effect, we also confirmed the direct cytotoxicity of RGS in inducing mitochondria-related apoptosis. Altogether, considering its PD-L1 inhibitory and cytotoxic effects, RGS could be a promising drug for CRC therapy.
    Keywords:  Anti-Tumor immunity; Autophagy; Colorectal cancer; Programmed cell death ligand 1; Rigosertib
    DOI:  https://doi.org/10.1016/j.canlet.2023.216422
  6. J Cell Physiol. 2023 Oct 10.
    Stearoyl-CoA desaturase 1 inhibition impairs triacylglycerol accumulation and lipid droplet formation in colorectal cancer cells.
    Zuzanna Tracz-Gaszewska, Adrian Sowka, Pawel Dobrzyn.
      Increases in fatty acid (FA) biosynthesis meet the higher lipid demand by intensely proliferating cancer cells and promoting their progression. Stearoyl-CoA desaturase 1 (SCD1) is the key enzyme in FA biosynthesis, converting saturated FA (SFA) into monounsaturated FA (MUFA). Increases in the MUFA/SFA ratio and SCD1 expression have been observed in cancers of various origins and correlate with their aggressiveness. However, much is still unknown about the SCD1-dependent molecular mechanisms that promote specific changes in metabolic pathways of cancer cells. The present study investigated the involvement of SCD1 in shaping glucose and lipid metabolism in colorectal cancer (CRC) cells. Excess FAs that derive from de novo lipogenesis are stored in organelles, called lipid droplets (LDs), mainly in the form of triacylglycerol (TAG) and cholesteryl esters. LD accumulation is associated with key features of cancer development and progression. Consistent with our findings, the pharmacological inhibition of SCD1 activity affects CRC cell viability and impairs TAG accumulation and LD formation in these cells through the activation of lipolytic and lipophagic pathways. We showed that SCD1 suppression affects crucial lipogenic processes that promote lipid accumulation in CRC cells but in a sterol regulatory element-binding protein 1-independent manner. We propose that adenosine monophosphate-activated protein kinase contributes to these changes through the activation of lipolysis and inhibition of TAG synthesis. We also provide evidence of the involvement of SCD1 in the regulation of glucose uptake and utilization in CRC cells. These findings underscore the importance of SCD1 in regulating cellular processes that promote cancer development and progression.
    Keywords:  SCD1; energetic metabolism; fatty acids; lipid droplets; lipolysis; lipophagy
    DOI:  https://doi.org/10.1002/jcp.31137
  7. Cell Death Dis. 2023 Oct 13. 14(10): 676
    Identification of ATF3 as a novel protective signature of quiescent colorectal tumor cells.
    Xi Lu, Lei Zhong, Emma Lindell, Margus Veanes, Jing Guo, Miao Zhao, Maede Salehi, Fredrik J Swartling, Xingqi Chen, Tobias Sjöblom, Xiaonan Zhang.
      Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.
    DOI:  https://doi.org/10.1038/s41419-023-06204-1
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒18 at 11:05.