bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–03–10
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. mTORC2-AKT signaling to PFKFB2 activates glycolysis that enhances stemness and tumorigenicity of intestinal epithelial cells.
  2. Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices.
  3. Loss of CDX2 and high COX2 (PTGS2) expression in metastatic colorectal cancer.
  4. KCTD15 acts as an anti-tumor factor in colorectal cancer cells downstream of the demethylase FTO and the m6A reader YTHDF2.
  5. Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines.
  6. Single-cell chromatin accessibility analysis reveals the epigenetic basis and signature transcription factors for the molecular subtypes of colorectal cancers.
  7. RIP140 regulates transcription factor HES1 oscillatory expression and mitogenic activity in colon cancer cells.
  8. Synergistic antitumor activity between HER2 antibody-drug conjugate and chemotherapy for treating advanced colorectal cancer.
  9. Identification of EGR4 as a prospective target for inhibiting tumor cell proliferation and a novel biomarker in colorectal cancer.
  10. The effects of metabolism on the immune microenvironment in colorectal cancer.
  1. FASEB J. 2024 Mar 15. 38(5): e23532
    mTORC2-AKT signaling to PFKFB2 activates glycolysis that enhances stemness and tumorigenicity of intestinal epithelial cells.
    Mengzhen Li, Xi Wu, Yuwei Pan, Manyu Song, Xu Yang, Jiuzhi Xu, Maksim V Plikus, Cong Lv, Lu Yu, Zhengquan Yu.
      Although elevated glycolysis has been widely recognized as a hallmark for highly proliferating cells like stem cells and cancer, its regulatory mechanisms are still being updated. Here, we found a previously unappreciated mechanism of mammalian target of rapamycin complex 2 (mTORC2) in regulating glycolysis in intestinal stem cell maintenance and cancer progression. mTORC2 key subunits expression levels and its kinase activity were specifically upregulated in intestinal stem cells, mouse intestinal tumors, and human colorectal cancer (CRC) tissues. Genetic ablation of its key scaffolding protein Rictor in both mouse models and cell lines revealed that mTORC2 played an important role in promoting intestinal stem cell proliferation and self-renewal. Moreover, utilizing mouse models and organoid culture, mTORC2 loss of function was shown to impair growth of gut adenoma and tumor organoids. Based on these findings, we performed RNA-seq and noticed significant metabolic reprogramming in Rictor conditional knockout mice. Among all the pathways, carbohydrate metabolism was most profoundly altered, and further studies demonstrated that mTORC2 promoted glycolysis in intestinal epithelial cells. Most importantly, we showed that a rate-limiting enzyme in regulating glycolysis, 6-phosphofructo-2-kinase (PFKFB2), was a direct target for the mTORC2-AKT signaling. PFKFB2 was phosphorylated upon mTORC2 activation, but not mTORC1, and this process was AKT-dependent. Together, this study has identified a novel mechanism underlying mTORC2 activated glycolysis, offering potential therapeutic targets for treating CRC.
    Keywords:  PFKFB2; glycolysis; intestinal stem cells; mTORC2; tumorigenesis
    DOI:  https://doi.org/10.1096/fj.202301833RR
  2. Science. 2024 Mar 08. 383(6687): eadi7342
    Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices.
    Matthew T Tierney, Lisa Polak, Yihao Yang, Merve Deniz Abdusselamoglu, Inwha Baek, Katherine S Stewart, Elaine Fuchs.
      Lineage plasticity-a state of dual fate expression-is required to release stem cells from their niche constraints and redirect them to tissue compartments where they are most needed. In this work, we found that without resolving lineage plasticity, skin stem cells cannot effectively generate each lineage in vitro nor regrow hair and repair wounded epidermis in vivo. A small-molecule screen unearthed retinoic acid as a critical regulator. Combining high-throughput approaches, cell culture, and in vivo mouse genetics, we dissected its roles in tissue regeneration. We found that retinoic acid is made locally in hair follicle stem cell niches, where its levels determine identity and usage. Our findings have therapeutic implications for hair growth as well as chronic wounds and cancers, where lineage plasticity is unresolved.
    DOI:  https://doi.org/10.1126/science.adi7342
  3. Ecancermedicalscience. 2024 ;18 1666
    Loss of CDX2 and high COX2 (PTGS2) expression in metastatic colorectal cancer.
    Álvaro M C Caldas, Warley A Nunes, Rodrigo Taboada, Marcelle G Cesca, Janaína N Germano, Rachel P Riechelmann.
      Lack of expression of the tumour suppressor gene caudal-type homeobox 2 (CDX2) associates with poor outcomes in early stage colorectal cancer (CRC). Yet its prognostic value in the context of other prognostic biomarkers in metastatic CRC (mCRC) is unknown. Overexpressed cyclooxygenase-2 (COX2) has been reported in advanced CRC. However, CDX2 and COX2 relationship in mCRC remains undetermined. We aimed to assess their expression in mCRC tumours from a clinically characterised cohort and their influence on overall survival (OS) and progression-free survival (PFS) in first line. Among 720 consecutive mCRC patients, 346 had tumour samples appropriate for tissue microarray assembly and immunohistochemistry analyses. Clinical and survival data were retrospectively assessed. Loss of CDX2 expression was detected in 27 (7.8%) samples, enriched in poorly differentiated tumours (20%; p < 0.01) and in those with the BRAF p.V600E variant (40%; p < 0.01). Most tumours (93.4%) expressed COX2. COX2-negative samples were enriched in poorly differentiated mCRC. In unadjusted analyses, median OS (p < 0.001) and median PFS (p < 0.05) were inferior for patients with CDX2-negative versus CDX2-positive tumours. In conclusion, loss of CDX2 was significantly associated with poorly differentiated mCRC and BRAF p.V600E allele and a prognostic marker of worse OS.
    Keywords:  BRAF; CDX2; COX2; chemotherapy; metastatic colorectal cancer
    DOI:  https://doi.org/10.3332/ecancer.2024.1666
  4. Commun Biol. 2024 Mar 04. 7(1): 262
    KCTD15 acts as an anti-tumor factor in colorectal cancer cells downstream of the demethylase FTO and the m6A reader YTHDF2.
    Fang-Yuan Zhang, Lin Wu, Tie-Ning Zhang, Huan-Huan Chen.
      Potassium Channel Tetramerization Domain Containing 15 (KCTD15) participates in the carcinogenesis of several solid malignancies; however, its role in colorectal cancer (CRC) remains unclear. Here we find that KCTD15 exhibits lower expression in CRC tissues as compared to para-carcinoma tissues. Tetracycline (tet)-induced overexpression and knockdown of KCTD15 confirms KCTD15 as an anti-proliferative and pro-apoptotic factor in CRC both in vitro and in xenografted tumors. N6-methyladenosine (m6A) is known to affect the expression, stabilization, and degradation of RNAs with this modification. We demonstrate that upregulation of fat mass and obesity-associated protein (FTO), a classical m6A eraser, prevents KCTD15 mRNA degradation in CRC cells. Less KCTD15 RNA is recognized by m6A 'reader' YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) in FTO-overexpressed cells. Moreover, KCTD15 overexpression decreases protein expression of histone deacetylase 1 (HDAC1) but increases acetylation of critical tumor suppressor p53 at Lys373 and Lys382. Degradation of p53 is delayed in CRC cells post-KCTD15 overexpression. We further show that the regulatory effects of KCTD15 on p53 are HDAC1-dependent. Collectively, we conclude that KCTD15 functions as an anti-growth factor in CRC cells, and its expression is orchestrated by the FTO-YTHDF2 axis. Enhanced p53 protein stabilization may contribute to KCTD15's actions in CRC cells.
    DOI:  https://doi.org/10.1038/s42003-024-05880-9
  5. iScience. 2024 Mar 15. 27(3): 109247
    Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines.
    Nobuhiko Ogasawara, Yoshihito Kano, Yosuke Yoneyama, Sakurako Kobayashi, Satoshi Watanabe, Sakura Kirino, Fausto D Velez-Bravo, Yourae Hong, Aleksandra Ostapiuk, Pavlo Lutsik, Iichiroh Onishi, Shinichi Yamauchi, Yui Hiraguri, Go Ito, Yusuke Kinugasa, Kenichi Ohashi, Mamoru Watanabe, Ryuichi Okamoto, Sabine Tejpar, Shiro Yui.
      In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.
    Keywords:  Cancer; Classification Description; Stem cell plasticity; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109247
  6. Cancer Discov. 2024 Mar 06.
    Single-cell chromatin accessibility analysis reveals the epigenetic basis and signature transcription factors for the molecular subtypes of colorectal cancers.
    Zhenyu Liu, Yuqiong Hu, Haoling Xie, Kexuan Chen, Lu Wen, Wei Fu, Xin Zhou, Fuchou Tang.
      Colorectal cancer (CRC) is a highly heterogeneous disease, with well-characterized subtypes based on genome, DNA methylome, and transcriptome signatures. To chart the epigenetic landscape of CRCs, we generated a high-quality single-cell chromatin accessibility atlas of epithelial cells for 29 patients. Abnormal chromatin states acquired in adenomas were largely retained in CRCs, which were tightly accompanied by opposite changes of DNA methylation. Unsupervised analysis on malignant cells revealed two epigenetic subtypes, exactly matching iCMS classification, and key iCMS-specific transcription factors were identified, including HNF4A, PPARA for iCMS2 tumors, and FOXA3, MAFK for iCMS3 tumors. Notably, subtype-specific TFs bind to distinct target gene sets and contribute to both inter-patient similarities and diversities for both chromatin accessibilities and RNA expressions. Moreover, we identified CpG-island methylator phenotypes and pinpointed chromatin state signatures and TF regulators for CIMP-High subtype. Our work systematically revealed the epigenetic basis of the well-known iCMS and CIMP classifications of CRCs.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1445
  7. Mol Oncol. 2024 Mar 08.
    RIP140 regulates transcription factor HES1 oscillatory expression and mitogenic activity in colon cancer cells.
    Nour Sfeir, Marilyn Kajdan, Stéphan Jalaguier, Sandrine Bonnet, Catherine Teyssier, Samuel Pyrdziak, Rong Yuan, Emilie Bousquet, Antonio Maraver, Florence Bernex, Nelly Pirot, Florence Boissière-Michot, Audrey Castet-Nicolas, Marion Lapierre, Vincent Cavaillès.
      The transcription factor receptor-interacting protein 140 (RIP140) regulates intestinal homeostasis and tumorigenesis through Wnt signaling. In this study, we investigated its effect on the Notch/HES1 signaling pathway. In colorectal cancer (CRC) cell lines, RIP140 positively regulated HES1 gene expression at the transcriptional level via a recombining binding protein suppressor of hairless (RBPJ)/neurogenic locus notch homolog protein 1 (NICD)-mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway, with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.
    Keywords:  HES1; Notch pathway; RIP140; colorectal cancer
    DOI:  https://doi.org/10.1002/1878-0261.13626
  8. Cell Death Dis. 2024 Mar 05. 15(3): 187
    Synergistic antitumor activity between HER2 antibody-drug conjugate and chemotherapy for treating advanced colorectal cancer.
    Hongfu Liu, Dongdong Zhou, Dongqin Liu, Xi Xu, Kai Zhang, Ruxia Hu, Peng Xiong, Changxin Wang, Xiangfu Zeng, Liefeng Wang, Shuyong Zhang.
      Colorectal cancer (CRC) is the third most common cancer associated with a poor prognosis. Effective targeted therapy alone or in combination for treating advanced CRC remains to be a major clinical challenge. Here, we propose the therapeutic efficacy and molecular mechanism underlying RC48, a FDA-approved anti-HER2 antibody conjugate via a cleavable linker to the microtubule inhibitor monomethyl auristatin E (MMAE), either alone or in combination with gemcitabine (GEM) in various models of HER2-positive advanced CRC. Our findings demonstrated that HER2 was widely expressed and located on the plasma membrane of CRC patient specimens, PDX xenograft tumors and cell lines. It confirmed that RC48 alone significantly targeted and eradicated HER2 positive CRC tumor in these models. Moreover, we screened a panel of FDA-approved first-line chemotherapy drugs in vitro. We found that GEM exhibited stronger antiproliferative activity compared to the other first-line anti-cancer agents. Furthermore, combination therapy of RC48 and GEM significantly showed synergetic antitumor activity in vitro and in vivo. To gain further mechanistic insights into the combination therapy, we performed RNA-seq analysis. The results revealed that combination treatment of RC48 and GEM regulated multiple signaling pathways, such as PI3K-AKT, MAPK, p53, Foxo, apoptosis, cell cycle and cell senescence, etc., to exert its antitumor activity in CRC cells. Collectively, these preclinical findings demonstrated that RC48 alone or combinational therapy exerted promising antitumor activity, and meriting the preclinical framework for combinational therapy of anti-HER2 drug conjugate drug and chemotherapy drugs for HER2-positive patients with advanced CRC.
    DOI:  https://doi.org/10.1038/s41419-024-06572-2
  9. Cancer Gene Ther. 2024 Mar 08.
    Identification of EGR4 as a prospective target for inhibiting tumor cell proliferation and a novel biomarker in colorectal cancer.
    Bangting Wang, Shijie Zhang, Haiyang Wang, Min Wang, Yuwen Tao, Mujie Ye, Zhining Fan, Yan Wang, Li Liu.
      EGR4 (Early Growth Response 4) is a member of the EGR family, involving in tumorigenesis. However, the function and action mechanism of EGR4 in the pathogenesis of colorectal cancer (CRC) remain unclear. To address this, we assessed the prognosis of CRC based on EGR4 using the Kaplan-Meier plotter tool and tissue microarray. The abundance of immunoinfiltration was evaluated through ssGSEA, TISIDB, and TIMER. In vitro experiments involving knockdown or overexpression of EGR4 were performed, and RNA-sequencing was conducted to explore potential mechanisms. Furthermore, we used oxaliplatin and 5-fluorouracil to validate the impact of EGR4 on chemo-resistance. Pan-cancer analysis and tissue microarray showed that EGR4 was highly expressed in CRC and significantly correlated with an unfavorable prognosis. Moreover, EGR4 expression was associated with immunoinfiltration and cancer-associated fibroblasts in the CRC microenvironment. Functional enrichment demonstrated that high-expressional EGR4 were involved in chromatin and nucleosome assembly. Additionally, EGR4 promoted the proliferation of CRC cells. Mechanistically, EGR4 upregulated TNFα to activate the NF-κB signaling pathway, and its knockdown reduced p65 nuclear translocation. Importantly, combining shEGR4 with oxaliplatin and 5-fluorouracil significantly inhibited CRC proliferation. Taken together, these findings provide new insights into the potential prognosis and therapeutic targets of EGR4 in CRC.
    DOI:  https://doi.org/10.1038/s41417-024-00743-1
  10. Cell Death Discov. 2024 Mar 07. 10(1): 118
    The effects of metabolism on the immune microenvironment in colorectal cancer.
    Xingzhao Chen, Zhiyuan Ma, Zhiqiang Yi, Enqin Wu, Zhengye Shang, Biguang Tuo, Taolang Li, Xuemei Liu.
      Colorectal cancer (CRC) is a malignancy that is widely prevalent worldwide. Due to its unsatisfactory treatment outcome and extremely poor prognosis, many studies on the molecular mechanisms and pathological mechanisms of CRC have been published in recent years. The tumor microenvironment (TME) is an extremely important feature of tumorigenesis and one of the hallmarks of tumor development. Metabolic reprogramming is currently a hot topic in tumor research, and studies on this topic have provided important insights into CRC development. In particular, metabolic reprogramming in cancer causes changes in the composition of energy and nutrients in the TME. Furthermore, it can alter the complex crosstalk between immune cells and associated immune factors, such as associated macrophages and T cells, which play important immune roles in the TME, in turn affecting the immune escape of tumors by altering immune surveillance. In this review, we summarize several metabolism-related processes affecting the immune microenvironment of CRC tumors. Our results showed that the immune microenvironment is regulated by metabolic reprogramming and influences the development of CRC.
    DOI:  https://doi.org/10.1038/s41420-024-01865-z
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