bims-instec 2024-12-15 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2024–12–15
fourteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Tuft cells promote human intestinal epithelium regeneration as reserve stem cells after irradiation.
Controlled aggregative assembly to form self-organizing macroscopic human intestine from induced pluripotent stem cells.
Loss of Notch dimerization perturbs intestinal homeostasis by a mechanism involving HDAC activity.
Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in KRAS-mutated colorectal cancer.
PPARα affects hepatic lipid homeostasis by perturbing necroptosis signals in the intestinal epithelium.
Integrative Metabolome and Transcriptome Analyses Provide Insights into PHGDH in Colon Cancer Organoids.
The Lyn/RUVBL1 Complex Promotes Colorectal Cancer Liver Metastasis by Regulating Arachidonic Acid Metabolism Through Chromatin Remodeling.
Effective Targeting of Colorectal Cancer Stem Cells by Inducing Differentiation Mediated by Low-Dose Vitamin C via β-Catenin Retention in the Cell Membrane.
Dynamic profiling of intra- and extra-cellular L/D-amino acids metabolism in colorectal cell and intestinal epithelial cell.
Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer.
Ubiquitin-conjugating enzyme E2T confers chemoresistance of colorectal cancer by enhancing the signal propagation of Wnt/β-catenin pathway in an ERK-dependent manner.
Integrating scRNA-seq and Visium HD for the analysis of the tumor microenvironment in the progression of colorectal cancer.
Villin-1 regulates ferroptosis in colorectal cancer progression.
YAP Promotes Chemoresistance to 5-FU in Colorectal Cancer Through mTOR/GLUT3 Axis.

Cell Regen. 2024 Dec 09. 13(1): 28

Tuft cells promote human intestinal epithelium regeneration as reserve stem cells after irradiation.

Yehua Li, Mengxian Zhang, Xianrun Ma, Ye-Guang Chen.

Intestinal epithelium regeneration is crucial for homeostatic maintenance of the intestinal functions. A recent study published in Nature uncovers tuft cells as an unexpected key player in the regenerative process. Human tuft cells, traditionally recognized for their involvement in immune defense and pathogen protection, were found to exhibit stem cell-like properties following radiation-induced injury. These cells not only resist damage but also have the ability to generate functional stem cells, promoting the repair of the intestinal epithelium. This finding suggests that tuft cells may function as a reserve pool of stem cells, essential for efficient intestinal regeneration after injury.

DOI: https://doi.org/10.1186/s13619-024-00214-w
Cell Rep Methods. 2024 Dec 03. pii: S2667-2375(24)00320-5. [Epub ahead of print] 100930

Controlled aggregative assembly to form self-organizing macroscopic human intestine from induced pluripotent stem cells.

Junichi Takahashi, Hady Yuki Sugihara, Shu Kato, Sho Kawasaki, Sayaka Nagata, Ryuichi Okamoto, Tomohiro Mizutani.

  Human intestinal organoids (HIOs) derived from human pluripotent stem cells (hPSCs) are promising resources for intestinal regenerative therapy as they recapitulate both endodermal and mesodermal components of the intestine. However, due to their hPSC-line-dependent mesenchymal development and spherical morphology, HIOs have limited applicability beyond basic research and development. Here, we demonstrate the incorporation of separately differentiated mesodermal and mid/hindgut cells into assembled spheroids to stabilize mesenchymal growth in HIOs. In parallel, we generate tubular intestinal constructs (assembled human intestinal tubules [a-HITs]) by leveraging the high aggregative property of assembled spheroids. Through rotational culture in a bioreactor, a-HITs self-organize to develop epithelium and supportive mesenchyme. Upon mesenteric transplantation, a-HITs mature into centimeter-scale tubular intestinal tissue with complex architectures. Our aggregation- and suspension-based approach offers basic technology for engineering tubular intestinal tissue from hPSCs, which could be ultimately applied to the generation of the human intestine for clinical application.

Keywords:  CP: stem cell; cell aggregation; human intestinal organoids; human pluripotent stem cells; regenerative medicine; self-organization; suspension culture; transplantation

DOI:  https://doi.org/10.1016/j.crmeth.2024.100930
PLoS Genet. 2024 Dec 12. 20(12): e1011486

Loss of Notch dimerization perturbs intestinal homeostasis by a mechanism involving HDAC activity.

Quanhui Dai, Kristina Preusse, Danni Yu, Rhett A Kovall, Konrad Thorner, Xinhua Lin, Raphael Kopan.

A tri-protein complex containing NICD, RBPj and MAML1 binds DNA as monomer or as cooperative dimers to regulate transcription. Mice expressing Notch dimerization-deficient alleles (NDD) of Notch1 and Notch2 are sensitized to environmental insults but otherwise develop and age normally. Transcriptomic analysis of colonic spheroids uncovered no evidence of dimer-dependent target gene miss-regulation, confirmed impaired stem cell maintenance in-vitro, and discovered an elevated signature of epithelial innate immune response to symbionts, a likely underlying cause for heightened sensitivity in NDD mice. TurboID followed by quantitative nano-spray MS/MS mass-spectrometry analyses in a human colon carcinoma cell line expressing either NOTCH2DD or NOTCH2 revealed an unbalanced interactome, with reduced interaction of NOTCH2DD with the transcription machinery but relatively preserved interaction with the HDAC2 interactome suggesting modulation via cooperativity. To ask if HDAC2 activity contributes to Notch loss-of-function phenotypes, we used the HDAC2 inhibitor Valproic acid (VPA) and discovered it could prevent the intestinal consequences of NDD and gamma secretase inhibitors (DBZ or DAPT) treatment in mice and spheroids, suggesting synergy between HDAC activity and pro-differentiation program in intestinal stem cells.

DOI: https://doi.org/10.1371/journal.pgen.1011486
Ther Adv Med Oncol. 2024 ;16 17588359241303302

Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in KRAS-mutated colorectal cancer.

Susmita Ghosh, Fan Fan, Reid Powell, Yong Sung Park, Clifford Stephan, E Scott Kopetz, Lee M Ellis, Rajat Bhattacharya.

   Background: KRAS is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with KRAS-mutated mCRC.
Objective: Our objective was to identify novel drug combinations that enhance MEK-inhibitor efficacy in patients with KRAS-mutated mCRC.
Design: In this study, we performed unbiased high-throughput screening (HTS) to identify drugs that enhance the efficacy of MEK inhibitors in vitro, and we validated the drugs' efficacy in vivo.
Methods: HTS was performed using three-dimensional CRC spheroids. Trametinib, the anchor drug, was probed with two "clinically ready" libraries of 252 drugs to identify effective drug combinations. The effects of the drug combinations on CRC cell proliferation and apoptosis were further validated using cell growth assays, flow cytometry, and biochemical assays. Proteomic and immunostaining studies were performed to determine the drugs' effects on molecular signaling and cell division. The effects of the drug combinations were examined in vivo using CRC patient-derived xenografts.
Results: HTS identified paclitaxel as being synergistic with trametinib. In vitro validation showed that, compared with monotherapies, this drug combination demonstrated strong inhibition of cell growth, reduced colony formation, and enhanced apoptosis in multiple KRAS-mutated CRC cell lines. Mechanistically, combining trametinib with paclitaxel led to alterations in signaling mediators that block cell-cycle progression. Trametinib also enhanced paclitaxel-mediated microtubule stability resulting in significantly higher defects in mitosis. Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS-mutant patient-derived xenograft mouse models.
Conclusion: Our data provide evidence supporting clinical trials of trametinib with paclitaxel as a novel therapeutic option for patients with KRAS-mutated, metastatic CRC.

Keywords:  KRAS; colorectal cancer; combination therapy; paclitaxel; trametinib

DOI:  https://doi.org/10.1177/17588359241303302
Acta Pharm Sin B. 2024 Nov;14(11): 4858-4873

PPARα affects hepatic lipid homeostasis by perturbing necroptosis signals in the intestinal epithelium.

Shufang Na, Yanjie Fan, HongLei Chen, Ling Li, Guolin Li, Furong Zhang, Rongyan Wang, Yafei Yang, Zixia Shen, Zhuang Peng, Yafei Wu, Yong Zhu, Zheqiong Yang, Guicheng Dong, Qifa Ye, Jiang Yue.

  Rapid turnover of the intestinal epithelium is a critical strategy to balance the uptake of nutrients and defend against environmental insults, whereas inappropriate death promotes the spread of inflammation. PPARα is highly expressed in the small intestine and regulates the absorption of dietary lipids. However, as a key mediator of inflammation, the impact of intestinal PPARα signaling on cell death pathways is unknown. Here, we show that Pparα deficiency of intestinal epithelium up-regulates necroptosis signals, disrupts the gut vascular barrier, and promotes LPS translocation into the liver. Intestinal Pparα deficiency drives age-related hepatic steatosis and aggravates hepatic fibrosis induced by a high-fat plus high-sucrose diet (HFHS). PPARα levels correlate with TRIM38 and MLKL in the human ileum. Inhibition of PPARα up-regulates necroptosis signals in the intestinal organoids triggered by TNF-α and LPS stimuli via TRIM38/TRIF and CREB3L3/MLKL pathways. Butyric acid ameliorates hepatic steatosis induced by intestinal Pparα deficiency through the inhibition of necroptosis. Our data suggest that intestinal PPARα is essential for the maintenance of microenvironmental homeostasis and the spread of inflammation via the gut-liver axis.

Keywords:  Butyric acid; Gut–liver axis; Intestine; LPS; Liver; NAFLD; Necroptosis; PPARα

DOI:  https://doi.org/10.1016/j.apsb.2024.08.021
Biosci Rep. 2024 Dec 13. pii: BSR20240842. [Epub ahead of print]

Integrative Metabolome and Transcriptome Analyses Provide Insights into PHGDH in Colon Cancer Organoids.

Lin Chen, Zhihui Dai, Yanfei Zhang, Huichao Sheng, Bin Hu, Jinlin Du, Jie Chang, Wenxia Xu, Yuqing Hu.

  As a rate-limiting enzyme in endogenous serine de novo synthesis pathway, PHGDH has been widely concerned about its role in a variety of tumors including colon cancer and the development of inhibitors. In our previous study, we studied PHGDH in colon cancer cell lines. However, with the development of personalized therapy, we realized that in scientific research, 2D cell lines lost a lot of original characteristic information during long-term culture, and the results obtained may not be enough to support the conclusion. Patient-derived tumor organoids maintain genomic stability and make up for information missing from cell lines due to monoclonal growth. Therefore, in our study, a colon cancer organoid with high PHGDH expression was selected, and was analyzed for transcriptomic and metabolomic changes through targeted inhibition of PHGDH. The results showed that inhibition of PHGDH significantly inhibited the proliferation of colon cancer organoids. The transcriptome, metabolome and combined omics analysis showed that the changes of colon cancer organoids after inhibition of PHGDH were mainly involved in PRSS1 and PRSS56, steroid hormone biosynthesis, phenylalanine metabolism, ascorbate and aldarate metabolism and tyrosine metabolism. In our study, the role of PHGDH in serine metabolism in colon cancer organoids was clarified by multi-omics analysis to provide new knowledge for in-depth understanding of serine metabolism and PHGDH function in colon cancer.

Keywords:  Colon cancer organoids; Metabolome; PHGDH; Transcriptome

DOI:  https://doi.org/10.1042/BSR20240842
Adv Sci (Weinh). 2024 Dec 12. e2406562

The Lyn/RUVBL1 Complex Promotes Colorectal Cancer Liver Metastasis by Regulating Arachidonic Acid Metabolism Through Chromatin Remodeling.

Zhenyu Zhang, Yina Gao, Yuanyuan Qian, Bowen Wei, Kexin Jiang, Zhiwei Sun, Feifan Zhang, Mingming Yang, Salem Baldi, Xiaoqi Yu, Yunfei Zuo, Shuangyi Ren.

  Liver metastasis is a common cause of death in colorectal cancer (CRC) patients, but epigenetic remodeling and metabolic reprogramming for CRC liver metastasis remain unclear. The study revealed that the Lyn/RUVBL1 complex is highly expressed in CRC and is closely correlated with liver metastasis. On the one hand, ATAC-seq and HiCut suggested that Lyn/RUVBL1 regulates the expression of TRIB3 through the POL II-mediated chromatin conformation of TRIB3 and thus the expression of β-catenin. This promotes the proliferation and migration of CRC through β-catenin-mediated upregulation of MMP9 and VEGF. On the other hand, metabolomics revealed that Lyn/RUVBL1 regulates the expression of PGE2 through the enzyme COX2, thereby promoting arachidonic acid (AA) metabolism. CUT-Tag showed that Lyn/RUVBL1 silencing reduces the H3K27ac level in the COX2 promoter. Then, it is found that COX2 is regulated by the transcription factor FOXA1. Lyn/RUVBL1 modulates AA metabolism by regulating the chromatin accessibility of FOXA1. AA metabolism promotes the metastasis of CRC by affecting β-catenin nuclear translocation and upregulating MMP9 and VEGF. These findings suggest that the Lyn/RUVBL1 complex mediates epigenetic remodeling to regulate the metabolic reprogramming of AA, highlighting its role in promoting the metastasis of CRC.

Keywords:  Lyn; RUVBL1; arachidonic acid metabolism; chromatin remodeling; colorectal cancer liver metastasis

DOI:  https://doi.org/10.1002/advs.202406562
J Cell Biochem. 2024 Dec 11. e30686

Effective Targeting of Colorectal Cancer Stem Cells by Inducing Differentiation Mediated by Low-Dose Vitamin C via β-Catenin Retention in the Cell Membrane.

Shanooja Shanavas, Utsav Sen, Rajkumar Banerjee, Sudheer Shenoy P, Bipasha Bose.

  Cancer stem cells (CSCs) are implicated as the underlying cause of tumor recurrence due to their refractoriness to conventional therapies. Targeting CSCs through novel approaches can hinder their survival and proliferation, potentially reducing the challenges associated with tumor relapse. Our previous study demonstrated that colorectal cancer stem cells (CR-CSCs) showed sensitivity to Vitamin C (Vit C), displaying a dose-responsive effect where low doses (2-10 µM) promoted cell proliferation while high doses induced cell death. In this study, we unraveled the mechanistic effects of low doses that, although induced proliferation, remarkably facilitated stemness reduction in HT-29 cell line-derived CR-CSCs. Our findings revealed that Vit C doses of 2 and 6 µM resulted in a reduction in stemness as evidenced by a reduced CD44+ cell population, representing CR-CSCs. The key finding was the remarkable increase in the expression of β-catenin protein following low-dose Vit C treatment, despite a reduction in stemness, accompanied by a mesenchymal to epithelial transition (MET). The sequestration of upregulated β-catenin via E-cadherin to the cell membrane was identified as a mechanism for reduced stemness, MET, and differentiation of CR-CSCs. Importantly, the epithelial phenotype induced by low-dose Vit C rendered CR-CSCs sensitive to conventional treatments, enhancing chemosensitivity to Cisplatin, Paclitaxel, and 5-Fluorouracil by 60%-90%. These findings suggest that low dose Vit C could serve as an adjuvant to conventional therapeutic strategies for targeting advanced colorectal cancer by sensitizing CR-CSCs to chemotherapy and potentially reducing tumor recurrence.

Keywords:  Vit C; ascorbic acid; cancer stem cell; colorectal cancer; epithelial to mesenchymal transition

DOI:  https://doi.org/10.1002/jcb.30686
J Pharm Biomed Anal. 2024 Dec 09. pii: S0731-7085(24)00664-2. [Epub ahead of print]255 116622

Dynamic profiling of intra- and extra-cellular L/D-amino acids metabolism in colorectal cell and intestinal epithelial cell.

Wenchan Deng, Rongrong Huang, Yuanjiang Pan, Cuirong Sun.

  The metabolism process of amino acids is closely related to the growth of normal and cancer cells. It is still not clear how L/D-configuration amino acids participate in the metabolism of colorectal cell. Herein, intra- and extra-cellular metabolic distribution of L/D-amino acids in colorectal cell (HCT116) and human normal intestinal epithelial cell (NCM460) were profiled utilizing HPLC-MS/MS coupled with a chiral probe. The results displayed the differential metabolic portrayal for the two cell lines. Compared with NCM460 cell, 13 kinds of significant differential amino acids were founded in a lower concentration within HCT116 cell, and L-Gln was even not detected for intra-cell; as for extra-cell culture medium, the HCT116 cell consumed more L-Gln, D-Phe and D-Leu, while L-Met was low ingested in HCT116 cell. L-Ala and Gly were excretion in both two cell lines, excepted L-Cit which was uptake in HCT116 and excretion in NCM460 cell. Furthermore, the dynamic changes of chiral amino acids displayed that phenylalanine, tyrosine and tryptophan biosynthesis and arginine biosynthesis is the major pathway for intra-cellular metabolites and extra-cellular metabolites, respectively. Moreover, with additional D-amino acids in culture medium, the results exhibited that high concentration of D-amino acids have no significant effect on the proliferation of NCM460 cell, but could influence the profiling of amino acids metabolites, and further affect the proliferation of HCT116 cell. This present work enhances the understanding of these differential amino acids metabolic network and depicts a dynamic process of metabolic dysregulation of HCT116 and NCM460 cell.

Keywords:  Cellular metabolism; Chiral amino acids; Colorectal cancer; HPLC-MS/MS

DOI:  https://doi.org/10.1016/j.jpba.2024.116622
Gut. 2024 Dec 10. pii: gutjnl-2024-332535. [Epub ahead of print]

Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer.

Ramani Soundararajan, Michelle M Maurin, Jetsen Rodriguez-Silva, Gunjan Upadhyay, Ashley J Alden, Siddabasave Gowda B Gowda, Michael J Schell, Mingli Yang, Noah Jhad Levine, Divyavani Gowda, Punith M Sundaraswamy, Shu-Ping Hui, Lance Pflieger, Heiman Wang, Jorge Marcet, Carolina Martinez, Robert David Bennett, Allen Chudzinski, Andreas Karachristos, Timothy M Nywening, Paul M Cavallaro, Matthew Linley Anderson, Robert J Coffey, Michael V Nebozhyn, Andrey Loboda, Domenico Coppola, Warren Jackson Pledger, Ganesh Halade, Timothy J Yeatman.

   BACKGROUND: Over a century ago, Virchow proposed that cancer represents a chronically inflamed, poorly healing wound. Normal wound healing is represented by a transitory phase of inflammation, followed by a pro-resolution phase, with prostaglandin (PGE2/PGD2)-induced 'lipid class switching' producing inflammation-quenching lipoxins (LXA4, LXB4).
OBJECTIVE: We explored if lipid dysregulation in colorectal cancers (CRCs) is driven by a failure to resolve inflammation.
DESIGN: We performed liquid chromatography and tandem mass spectrometry (LC-MS/MS) untargeted analysis of 40 human CRC and normal paired samples and targeted, quantitative analysis of 81 human CRC and normal paired samples. We integrated analysis of lipidomics, quantitative reverse transcription-PCR, large scale gene expression, and spatial transcriptomics with public scRNASEQ data to characterize pattern, expression and cellular localisation of genes that produce and modify lipid mediators.
RESULTS: Targeted, quantitative LC-MS/MS demonstrated a marked imbalance of pro-inflammatory mediators, with a dearth of resolving lipid mediators. In tumours, we observed prominent over-expression of arachidonic acid derivatives, the genes encoding their synthetic enzymes and receptors, but poor expression of genes producing pro-resolving synthetic enzymes and resultant lipoxins (LXA4, LXB4) and associated receptors. These results indicate that CRC is the product of defective lipid class switching likely related to inadequate or ineffective levels of PGE2/PGD2.
CONCLUSION: We show that the lipidomic profile of CRC tumours exhibits a distinct pro-inflammatory bias with a deficiency of endogenous resolving mediators secondary to defective lipid class switching. These observations pave the way for 'resolution medicine', a novel therapeutic approach for inducing or providing resolvins to mitigate the chronic inflammation driving cancer growth and progression.

Keywords:  COLORECTAL CANCER; EICOSANOIDS; GENE EXPRESSION; INFLAMMATION; LIPID METABOLISM

DOI:  https://doi.org/10.1136/gutjnl-2024-332535
Chem Biol Interact. 2024 Dec 10. pii: S0009-2797(24)00493-9. [Epub ahead of print] 111347

Ubiquitin-conjugating enzyme E2T confers chemoresistance of colorectal cancer by enhancing the signal propagation of Wnt/β-catenin pathway in an ERK-dependent manner.

Bo Liu, Ruiting Liu, Xiaolong Zhang, Lifei Tian, Zeyu Li, Jiao Yu.

  Chemotherapy is a major therapeutic option for colorectal cancer; however, the frequently acquired chemoresistance greatly limits the treatment efficacy of chemotherapeutic agents. Ubiquitin-conjugating enzyme E2T (UBE2T) is emerging as a key player in the development of therapy resistance. However, whether UBE2T participates in the acquisition of chemoresistance in colorectal cancer remains undetermined. The present work aimed to specify the role of UBE2T in the development of chemoresistance in colorectal cancer and decipher any potential underlying mechanisms. Significant up-regulation of UBE2T was observed in the clinical specimens of chemoresistant colorectal cancer patients compared with chemosensitive patients. Compared with parental cells, the levels of UBE2T were also dramatically elevated in oxaliplatin (OXA)- and 5-fluorouracil (5-FU)-resistant colorectal cancer cells. Knockout of UBE2T rendered OXA- and 5-FU-resistant cells sensitive to OXA and 5-FU, respectively. Re-expression of UBE2T restored the chemoresistance of UBE2T-knockout OXA- and 5-FU-resistant cells. Mechanistically, phosphorylated GSK-3β, active β-catenin, c-myc and cyclin D1 levels were decreased in UBE2T-knockout OXA- and 5-FU-resistant cells, which were reversed by the re-expression of UBE2T. Moreover, knockout of UBE2T reduced the activation of ERK. The inhibition of ERK reversed the promotion effect of UBE2T on Wnt/β-catenin pathway. In vivo xenograft experiments demonstrated that knockout of UBE2T rendered the subcutaneous tumors formed by OXA-resistant cells sensitive to OXA. To conclude, UBE2T confers chemoresistance of colorectal cancer by boosting the signal propagation of the Wnt/β-catenin pathway in an ERK-dependent manner. Therefore, UBE2T could be a potential target for overcoming chemoresistance in the treatment of colorectal cancer.

Keywords:  Chemoresistance; ERK; Wnt; colorectal cancer

DOI:  https://doi.org/10.1016/j.cbi.2024.111347
Int Immunopharmacol. 2024 Dec 05. pii: S1567-5769(24)02274-4. [Epub ahead of print]145 113752

Integrating scRNA-seq and Visium HD for the analysis of the tumor microenvironment in the progression of colorectal cancer.

Chun Wang, Mengying Lu, Cuimin Chen, Jiajun Chen, Yusi Cai, Hao Wang, Lili Tao, Weihua Yin, Jiakang Chen.

   BACKGROUND: Colorectal cancer (CRC) development is a complex, multi-stage process, transitioning from normal to adenomatous tissue, and then to invasive carcinoma. Despite research, there's a knowledge gap on using high-resolution spatial omics to understand CRC's tumor microenvironment dynamics.
METHODS: We used single-cell transcriptomics to study major biological changes and cell interactions in CRC progression. Additionally, high-resolution spatial transcriptomics helped us examine the spatial distribution of cells with significant pathway changes, offering insights into the tumor microenvironment's development throughout CRC stages.
RESULTS: In the progression of CRC, plasma cells, neutrophils, and fibroblasts exhibit the most significant changes in hallmark pathways, while epithelial cells show the most pronounced alterations in metabolic pathways. We also identified a population of NOTUM + epithelial cells and IGHG1/3 + plasma cells that are concentrated at the boundary between normal tissue and adenomas. Pathway analysis further suggests that these NOTUM + cells activate numerous cancer-related pathways, despite the absence of significant pathological morphological changes. Additionally, we conducted a targeted drug prediction analysis to identify potential therapeutic agents for NOTUM-expressing epithelial cells.
CONCLUSIONS: Analyzing scRNA-seq and Visium HD data, we found that IGHG1/3 + plasma cells and tumor-associated neutrophil (TANs) may significantly affect colorectal tissue transformation from normal to adenoma and carcinoma. These cells are concentrated at the transition between normal and adenomatous tissue. We also found NOTUM-expressing cells at the edge of normal and adenomatous areas, possibly indicating a morphological transition as normal cells evolve into adenoma cells.

Keywords:  CRC; NOTUM; Neutrophil; Pathology; Plasma cell; ScRNA-seq; Visium HD

DOI:  https://doi.org/10.1016/j.intimp.2024.113752
FEBS J. 2024 Dec 10.

Villin-1 regulates ferroptosis in colorectal cancer progression.

Bangli Hu, Yixin Yin, Birong Zhang, Siqi Li, Kezhi Li, You Zhou, Qinghua Huang.

  Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Despite extensive research, the mechanistic underpinnings driving CRC progression remain largely unknown. As a fundamental component of the brush border cytoskeleton, villin-1 (VIL1) acts as a marker for intestinal cell differentiation and maturation. Through a comprehensive transcriptomics analysis of eight studies (total sample: n = 1952), we consistently observed significant upregulation of VIL1 expression in CRC tumors compared with adjacent normal tissue. In our independent cohort, this notable upregulation has been further validated at both mRNA and protein levels in colon tumor tissues, relative not only to adjacent normal tissue but also to normal controls. Our data show that VIL1 promotes proliferation and migration while inhibiting apoptosis. Conversely, knockout of VIL1 suppresses proliferation and migration while inducing apoptosis. Mechanistically, we reveal that knocking out VIL1 activates ferroptosis and inhibits the migration of CRC cells, while overexpressing VIL1 yields the opposite effects, and vice versa. Additionally, VIL1 binds to Nuclear factor NF-kappa-B p105 subunit (NF-κB) and controls NF-κB expression. In vivo, overexpressing VIL1 inhibits ferroptosis, and induces the expression of NF-κB and lipocalin 2 (LCN2), thereby promoting CRC tumor growth. Thus, we have identified the VIL1/NF-κB axis as a pivotal regulator of CRC progression through ferroptosis modulation, unveiling VIL1 as a promising therapeutic target for CRC treatment via ferroptosis. Our study offers novel avenues for exploring the therapeutic potential of ferroptosis in CRC management, emphasizing the high potential of VIL1 in regulating colorectal tumorigenesis.

Keywords:  colorectal cancer; ferroptosis; villin‐1

DOI:  https://doi.org/10.1111/febs.17350
J Cancer. 2024 ;15(20): 6784-6797

YAP Promotes Chemoresistance to 5-FU in Colorectal Cancer Through mTOR/GLUT3 Axis.

Qixuan Xu, Zhesi Jin, Zhen Yuan, Zhiyuan Yu, Jingwang Gao, Ruiyang Zhao, Hanghang Li, Huiguang Ren, Bo Cao, Bo Wei, Linhua Jiang.

  Background: Although chemoresistance constitutes a significant barrier to the effectiveness of chemotherapy in colorectal cancer (CRC), its precise mechanisms remain unclear. YAP functions as an oncogene in various malignancies. However, the relationship between YAP and chemoresistance in CRC needs clarification. Methods: The expression level of YAP in CRC tissues was assessed through immunohistochemistry (IHC), and the impact of YAP on CRC cell chemoresistance was evaluated using the Cell Counting Kit-8, EdU, and flow cytometry assays. Meanwhile, tumor proliferation was assessed in vivo by analyzing the expression of PCNA and Ki-67 in subcutaneous tumors via IHC. In addition, the TUNEL assay was employed to evaluate tumor apoptosis levels and western blot was utilized to detect the mTOR/GLUT3 pathway-related protein expression to provide insights into the underlying mechanism. Results: YAP was highly expressed in CRC tissues and correlated with patient prognosis and clinicopathological features. Bioinformatic analysis based on the TCGA database revealed that YAP was associated with DNA replication, glycolysis, and the mTOR pathway. Meanwhile, YAP could enhance chemoresistance and glycolysis in CRC cells both in vitro and in vivo. Additional mechanistic experiments unveiled that YAP promoted CRC cell chemoresistance via the mTOR/GLUT3 axis. Conclusion: This study validated the role of YAP as an oncogene in CRC, as it promoted chemoresistance through the mTOR/GLUT3 axis. These results suggested YAP as a potential target for promoting the efficacy of chemotherapy in patients with CRC.

Keywords:  GLUT3.; YAP; chemoresistance; colorectal cancer; glycolysis; mTOR pathway

DOI:  https://doi.org/10.7150/jca.100179