bims-instec 2024-11-17 papers

bims-instec

Biomed News

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

Issue of 2024–11–17
twenty papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

High mobility group A1 (HMGA1) promotes the tumorigenesis of colorectal cancer by increasing lipid synthesis.
Establishment of Patient-Derived Organoids from Colorectal Cancer Resection Samples.
Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration.
Identification of feature genes in intestinal epithelial cell types.
Modeling adenoma-carcinoma progression from a single MLH1-knockout cell via colon organoids.
Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts.
Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties.
Colorectal carcinoma progression is not influenced by the pseudokinase PEAK1.
Fatty acid dehydratase HACD3 poses protein kinase activity and promotes the malignant progression of colorectal cancer.
High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids.
Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters in collective cell migration of epithelial cells.
PCYT2 inhibits epithelial-to-mesenchymal transition in colorectal cancer by elevating YAP1 phosphorylation.
Identifying colorectal cancer subtypes and establishing a prognostic model using metabolic plasticity and ferroptosis genes.
Metabolic landscape of disseminated cancer dormancy.
Estrogen-mediated inhibition of purine metabolism and cell cycle arrest as a novel therapeutic approach in colorectal cancer.
Dietary omega-3 (ω-3) fatty acids mitigate intestinal barrier integrity alterations in mice fed a high-fat diet: Implications for pancreatic carcinogenesis.
MDM4 inhibits ferroptosis in p53 mutant colon cancer via regulating TRIM21/GPX4 expression.
Protective role of short-chain fatty acids on intestinal oxidative stress induced by TNF-α.
RNF4 mediated degradation of PDHA1 promotes colorectal cancer metabolism and metastasis.
KRAS inhibitors may prevent colorectal cancer metachronous metastasis by suppressing TGF‑β mediated epithelial‑mesenchymal transition.

Nat Commun. 2024 Nov 15. 15(1): 9909

High mobility group A1 (HMGA1) promotes the tumorigenesis of colorectal cancer by increasing lipid synthesis.

Yuan Zhao, Meng-Jie Liu, Lei Zhang, Qi Yang, Qian-Hui Sun, Jin-Rong Guo, Xin-Yuan Lei, Kai-Yue He, Jun-Qi Li, Jing-Yu Yang, Yong-Ping Jian, Zhi-Xiang Xu.

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the high energy and biosynthetic demands required for their proliferation. High mobility group A1 (HMGA1) is a structural transcription factor and frequently overexpressed in human colorectal cancer (CRC). Here, we show that HMGA1 promotes CRC progression by driving lipid synthesis in a AOM/DSS-induced CRC mouse model. Using conditional knockout (Hmga1△IEC) and knock-in (Hmga1IEC-OE/+) mouse models, we demonstrate that HMGA1 enhances CRC cell proliferation and accelerates tumor development by upregulating fatty acid synthase (FASN). Mechanistically, HMGA1 increases the transcriptional activity of sterol regulatory element-binding protein 1 (SREBP1) on the FASN promoter, leading to increased lipid accumulation in intestinal epithelial cells. Moreover, a high-fat diet exacerbates CRC progression in Hmga1△IEC mice, while pharmacological inhibition of FASN by orlistat reduces tumor growth in Hmga1IEC-OE/+ mice. Our findings suggest that targeting lipid metabolism could offer a promising therapeutic strategy for CRC.

DOI: https://doi.org/10.1038/s41467-024-54400-0
Methods Mol Biol. 2024 Nov 10.

Establishment of Patient-Derived Organoids from Colorectal Cancer Resection Samples.

Didem Seven, Szilvia Baron, Henner F Farin.

  Colorectal cancer (CRC) organoids can serve as powerful preclinical cell models that accurately reflect individual tumor characteristics. Establishing a patient-derived CRC biobank facilitates a wide range of applications, including basic oncology research, new drug discovery, drug testing, and personalized medicine. This chapter details the process of generation of organoids from surgical samples of primary and metastatic CRC as well as from tumor adjacent normal colon tissues. Furthermore, best practices for cultivation and cryostorage of CRC organoids are described.

Keywords:  Biobank; Colon organoids; Colorectal cancer; Patient-derived organoids; Stem cells

DOI:  https://doi.org/10.1007/7651_2024_575
Nat Cell Biol. 2024 Nov 15.

Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration.

Mardi Fink, Kizito Njah, Shyam J Patel, David P Cook, Vanessa Man, Francesco Ruso, Arsheen Rajan, Masahiro Narimatsu, Andreea Obersterescu, Melanie J Pye, Daniel Trcka, Kin Chan, Arshad Ayyaz, Jeffrey L Wrana.

Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages. While revSC genes themselves are accessible throughout homeostatic epithelia, damage-induced remodelling of chromatin in the crypt converges on Hippo and the transforming growth factor-beta (TGFβ) signalling pathway, which we show is transiently activated and directly induces functional revSCs. Combinatorial gene expression analysis further suggests multiple sources of revSCs, and we demonstrate TGFβ can reprogramme enterocytes, goblet and paneth cells into revSCs and show individual revSCs form organoids. Despite this, loss of TGFβ signalling yields mild regenerative defects, whereas interference in both Hippo and TGFβ leads to profound defects and death. Intestinal regeneration is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support epithelial reprogramming and robust intestinal repair.

DOI: https://doi.org/10.1038/s41556-024-01550-4
Cell Regen. 2024 Nov 15. 13(1): 24

Identification of feature genes in intestinal epithelial cell types.

Ruoyu Lou, Wanlu Song, Shicheng Yu, Xiaodan Wang, Yuan Liu, Ye-Guang Chen, Yalong Wang.

  The intestine, is responsible for food digestion, nutrient absorption, endocrine secretion, food residue excretion, and immune defense. These function performances are based on the intricate composition of intestinal epithelial cells, encompassing differentiated mature cells, rapidly proliferative cells, and intestinal stem cells. Although the characteristics of these cell types are well-documented, in-depth exploration of their representative markers and transcription factors is critical for comprehensive cell fate trajectory analysis. Here, we unveiled the feature genes in different cell types of the human and mouse gut through single-cell RNA sequencing analysis. Further, the locations of some specific transcription factors and membrane proteins were determined by immunofluorescence staining, and their role in regulating the proliferation and differentiation of intestinal epithelial cells were explored by CRISPR/Cas9 knockout. Therefore, this study not only reports new markers for various intestinal epithelial cell types but also elucidates the involvement of relevant genes in the determination of epithelial cell fate and maintenance of stem cell homeostasis, which facilitates the tracing and functional elucidation of intestinal epithelial cells.

Keywords:  Cell markers; Feature genes; Intestinal epithelium; Stem cell

DOI:  https://doi.org/10.1186/s13619-024-00208-8
Nat Cancer. 2024 Nov 08.

Modeling adenoma-carcinoma progression from a single MLH1-knockout cell via colon organoids.

DOI: https://doi.org/10.1038/s43018-024-00842-w
Nat Commun. 2024 Nov 11. 15(1): 9139

Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts.

Umberto Perron, Elena Grassi, Aikaterini Chatzipli, Marco Viviani, Emre Karakoc, Lucia Trastulla, Lorenzo M Brochier, Claudio Isella, Eugenia R Zanella, Hagen Klett, Ivan Molineris, Julia Schueler, Manel Esteller, Enzo Medico, Nathalie Conte, Ultan McDermott, Livio Trusolino, Andrea Bertotti, Francesco Iorio.

Patient-derived xenografts (PDXs) are tumour fragments engrafted into mice for preclinical studies. PDXs offer clear advantages over simpler in vitro cancer models - such as cancer cell lines (CCLs) and organoids - in terms of structural complexity, heterogeneity, and stromal interactions. Here, we characterise 231 colorectal cancer PDXs at the genomic, transcriptomic, and epigenetic levels, along with their response to cetuximab, an EGFR inhibitor used clinically for metastatic colorectal cancer. After evaluating the PDXs' quality, stability, and molecular concordance with publicly available patient cohorts, we present results from training, interpreting, and validating the integrative ensemble classifier CeSta. This model takes in input the PDXs' multi-omic characterisation and predicts their sensitivity to cetuximab treatment, achieving an area under the receiver operating characteristics curve > 0.88. Our study demonstrates that large PDX collections can be leveraged to train accurate, interpretable drug sensitivity models that: (1) better capture patient-derived therapeutic biomarkers compared to models trained on CCL data, (2) can be robustly validated across independent PDX cohorts, and (3) could contribute to the development of future therapeutic biomarkers.

DOI: https://doi.org/10.1038/s41467-024-53163-y
Elife. 2024 Nov 13. pii: RP97279. [Epub ahead of print]13

Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties.

Jae Hun Shin, Jooyoung Park, Jaechul Lim, Jaekwang Jeong, Ravi K Dinesh, Stephen E Maher, Jeonghyun Kim, Soyeon Park, Jun Young Hong, John Wysolmerski, Jungmin Choi, Alfred L M Bothwell.

  Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here, we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single-cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9, a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.

Keywords:  DKK2; Paneth cell properties; cancer biology; colon cancer; metastasis; mouse

DOI:  https://doi.org/10.7554/eLife.97279
Sci Rep. 2024 11 12. 14(1): 27663

Colorectal carcinoma progression is not influenced by the pseudokinase PEAK1.

Alba Zuidema, Paul Atherton, Sabine van der Poel, Maaike Kreft, Ji-Ying Song, Martine Bierbooms, Sophie Verhoeven, Chrysoula Papagianni, Lona Kroese, Rahmen Bin Ali, Ivo Huijbers, Beatriz Carvalho, Arnoud Sonnenberg.

  The scaffold protein PEAK1 acts downstream of integrin adhesion complexes and the epidermal growth factor receptor, orchestrating signaling events that control cell proliferation and cytoskeletal remodeling. In this study we investigated the role of PEAK1 in colorectal carcinoma (CRC) progression using various in vitro and in vivo models to replicate the stepwise pathogenesis of CRC. While we observed a cell-type specific role for PEAK1 in the proliferation and in human CRC cell lines in vitro, our in vivo experiments using different CRC mouse models driven by loss of Apc, with or without oncogenic Kras or Pten loss suggest that PEAK1 does not significantly contribute to tumor formation in vivo. However, the survival time of Peak1-/- mice in the Apcfl/+ model appeared to be slightly increased. Furthermore, PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization and lumenization. Given that the Caco-2 cells harbor mutations in the tumor suppressors APC and β-CATENIN, but not in other tumor suppressors or in proto-oncogenes, we conclude that the PEAK1's impact on colon carcinogenesis is limited, potentially playing a role in the initial stage of the adenoma to carcinoma progression.

Keywords:  APC; Colorectal carcinoma; EGF; KRAS; PEAK1; PTEN

DOI:  https://doi.org/10.1038/s41598-024-78776-7
Int J Biol Macromol. 2024 Nov 13. pii: S0141-8130(24)08223-0. [Epub ahead of print] 137414

Fatty acid dehydratase HACD3 poses protein kinase activity and promotes the malignant progression of colorectal cancer.

Xiaoying Wang, Qindan Du, Jiayao Chen, Rong Wang, Yong Zhao, Sihui Liu, Yong Q Chen.

  HACD3 is a member belonging to the very long-chain fatty acid dehydratase family. However, little is known about HACD3's function besides its weak dehydratase activity. The current study aims to investigate the potential role of HACD3 in Colorectal Cancer (CRC). The study evaluates HACD3 expression in CRC patient samples. Moreover, the study investigates in vitro cell proliferation, colony formation, invasion, migration, and cell cycle progression on HACD3 knockdown and overexpressing CRC cells, along with in vivo tumorigenesis within NSG mice, Hacd3-/-; ApcMin/+ mice and Hacd3ΔIEC; ApcMin/+mice. The study identifies the molecular target(s) of HACD3 via phosphoproteomics, followed by biological assay verification. The study identifies that HACD3 is highly expressed in CRC tissues and promotes the malignant progression of cancer cells. Additionally, HACD3 interacts with CDK2, leading to CDK2 T160 phosphorylation via a domain between amino acids 298-324 of HACD3. Thus, fatty acid dehydratase HACD3 possesses protein kinase activity and stimulates tumorigenesis, partly by activating the CDK2 pathway. Therefore, inhibiting HACD3 could facilitate CRC treatment.

Keywords:  CDK2; Colorectal cancer; HACD3; Protein kinase

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137414
BJC Rep. 2024 Apr 03. 2(1): 29

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids.

Kirti K Iyer, Dennis Poel, Anne Miggelenbrink, Wouter Kerkhof, Jorien Janssen, Lotte Bakkerus, Loek de Jong, Erik van den Hombergh, Iris D Nagtegaal, Daniele V F Tauriello, Nielka P van Erp, Henk M W Verheul.

BACKGROUND: Most tyrosine kinase inhibitors (TKIs) have failed in clinical trials for metastatic colorectal cancer (mCRC). To leverage the additional lower-affinity targets that most TKIs have, high-dose regimens that trigger efficacy are explored. Here, we studied unprecedented drug exposure-response relationships in vitro using mCRC patient-derived tumour organoids (PDTOs).
METHODS: We investigated the cytotoxic anti-tumour effect of high-dose, short-term (HDST) TKI treatment on 5 PDTOs. Sunitinib, cediranib and osimertinib were selected based on favourable physicochemical and pharmacokinetic properties. Intra-tumoroid TKI concentrations were measured using a clinically validated LC/MS-MS method. Cell death was determined using an enzyme activity assay, immunofluorescent staining and western blotting.
RESULTS: Most PDTOs tested were sensitive to sunitinib and cediranib, but all to osimertinib. Furthermore, HDST osimertinib treatment effectively blocks organoid growth. This treatment led to markedly elevated intra-tumoroid TKI concentrations, which correlated with PDTO sensitivity. Mechanistically, HDST osimertinib treatment induced apoptosis in treated PDTOs.
CONCLUSION: Our work provides a better understanding of TKI exposure vs response and can be used to determine patient-specific sensitivity. Additionally, these results may guide both mechanistic elucidation in organotypic translational models and the translation of target drug exposure to clinical dosing strategies. Moreover, HDST osimertinib treatment warrants clinical exploration for mCRC.

DOI: https://doi.org/10.1038/s44276-024-00042-0
Cell Rep. 2024 Nov 14. pii: S2211-1247(24)01337-8. [Epub ahead of print]43(11): 114986

Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters in collective cell migration of epithelial cells.

Eriko Deguchi, Shuhao Lin, Daiki Hirayama, Kimiya Matsuda, Akira Tanave, Kenta Sumiyama, Shinya Tsukiji, Tetsuhisa Otani, Mikio Furuse, Alexander Sorkin, Michiyuki Matsuda, Kenta Terai.

  Canonical epidermal growth factor (EGF) receptor (EGFR) activation involves the binding of seven EGFR ligands (EGFRLs); however, their extracellular dynamics remain elusive. Here, employing fluorescent probes and a tool for triggering ectodomain shedding, we show that epiregulin (EREG), a low-affinity EGFRL, rapidly and efficiently activates EGFR in Madin-Darby canine kidney (MDCK) epithelial cells and mouse epidermis. During collective cell migration, EGFR and extracellular signal-regulated kinase (ERK) activation waves propagate in an a disintegrin and metalloprotease 17 (ADAM17) sheddase- and EGFRL-dependent manner. Upon induced EGFRL shedding, low-affinity ligands EREG and amphiregulin (AREG) mediate faster and broader ERK waves than high-affinity ligands. Tight/adherens junction integrity is essential for ERK activation propagation, suggesting that tight intercellular spaces prefer the low-affinity EGFRLs for efficient signal transmission. In EREG-deficient mice, ERK wave propagation and cell migration were impaired during skin wound repair. We additionally show that heparin-binding EGF-like growth factor (HBEGF) primarily promotes surrounding cell motility. Our findings underscore the pivotal role of low-affinity EGFRLs in rapid intercellular signal transmission.

Keywords:  ADAM17; CP: Cell biology; EGFR ligand; EREG; ERK activation wave; FRET; chemogenetics; collective cell migration; transgenic mice

DOI:  https://doi.org/10.1016/j.celrep.2024.114986
JCI Insight. 2024 Nov 12. pii: e178823. [Epub ahead of print]

PCYT2 inhibits epithelial-to-mesenchymal transition in colorectal cancer by elevating YAP1 phosphorylation.

Lian Zhou, Su Zhang, Lingli Wang, Xueqin Liu, Xuyang Yang, Lei Qiu, Ying Zhou, Qing Huang, Yang Meng, Xue Lei, Linda Wen, Junhong Han.

  Metabolic reprogramming is a common feature in tumor progression and metastasis. Like proteins, lipids can transduce signals through lipid-protein interactions. During tumor initiation and metastasis, dysregulation of the Hippo pathway plays a critical role. Specifically, the inhibition of YAP1 phosphorylation leads to the relocation of YAP1 to the nucleus to activate transcription of genes involved in metastasis. Although recent studies reveal the involvement of phosphatidylethanolamine (PE) synthesis enzyme phosphoethanolamine cytidylyltransferase 2 (PCYT2) in tumor chemoresistance, the impact of PCYT2 on tumor metastasis remains elusive. Here, we showed that PCYT2 was significantly downregulated in metastatic colorectal cancer (CRC) and acted as a tumor metastasis suppressor. Mechanistically, PCYT2 increased the interaction between PEBP1 and YAP1-phosphatase PPP2R1A, thus disrupting PPP2R1A-YAP1 association. As a result, phosphorylated-YAP1 levels were increased, leading to YAP1 degradation through the ubiquitin protease pathway. YAP1 reduction in the nucleus repressed the transcription of ZEB1 and Snail2, eventually resulting in metastasis suppression. Our work provides insight into the role of PE synthesis in regulating metastasis and presents PCYT2 as a potential therapeutic target for CRC.

Keywords:  Cancer; Cell biology; Colorectal cancer; Oncology; Tumor suppressors

DOI:  https://doi.org/10.1172/jci.insight.178823
Sci Rep. 2024 11 08. 14(1): 27277

Identifying colorectal cancer subtypes and establishing a prognostic model using metabolic plasticity and ferroptosis genes.

Jingwen Guan, Simin Min, Yan Xia, Zhiguo Guo, Xiaolan Zhou.

  Metabolic plasticity and ferroptosis are essential for colorectal cancer (CRC) progression. The effects and prognostic value of metabolic plasticity- and ferroptosis-related genes (MPFRGs) in CRC remain unclear. We established a prognostic model for CRC patients by identifying important genes in metabolic plasticity and ferroptosis. Data of CRC patients were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus; MPFRG data were obtained from GeneCards and FerrDb. We performed functional (to explore differences between the two metabolic subtypes) and single-sample gene set (to assess the immune environment) enrichment analyses. Immunophenotype, tumor immunological dysfunction, and exclusion scores were assessed to determine patient immune responses. A least absolute shrinkage and selection operator-Cox regression model comprising 10 significant differentially expressed genes of metabolic plasticity and ferroptosis (MPFDEGs) was constructed using TCGA training cohort and validated using the GSE17536 and GSE39582 datasets. We established a nomogram comprising metabolic plasticity- and ferroptosis-based signatures, revealing the clinical application and potential molecular mechanisms underlying the role of MPFRGs in CRC. Our model (developed based on 10 MPFDEGs) is efficient for calculating the overall survival of CRC patients. Our findings provide new strategies for the clinical management and individualized treatment of these patients.

Keywords:  Bioinformatics; Colorectal cancer; Ferroptosis; Immune infiltration; Metabolic plasticity; Prognostic factor

DOI:  https://doi.org/10.1038/s41598-024-78505-0
Trends Cancer. 2024 Nov 06. pii: S2405-8033(24)00224-3. [Epub ahead of print]

Metabolic landscape of disseminated cancer dormancy.

Stanislav Drapela, Bruna M Garcia, Ana P Gomes, Ana Luísa Correia.

  Cancer dormancy is a phenomenon defined by the entry of cancer cells into a reversible quiescent, nonproliferative state, and represents an essential part of the metastatic cascade responsible for cancer recurrence and mortality. Emerging evidence suggests that metabolic reprogramming plays a pivotal role in enabling entry, maintenance, and exit from dormancy in the face of the different environments of the metastatic cascade. Here, we review the current literature to understand the dynamics of metabolism during dormancy, highlighting its fine-tuning by the host micro- and macroenvironment, and put forward the importance of identifying metabolic vulnerabilities of the dormant state as therapeutic targets to eradicate recurrent disease.

Keywords:  dormancy; metabolism; metastasis; metastatic microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2024.10.005
Mol Cell Endocrinol. 2024 Nov 13. pii: S0303-7207(24)00270-3. [Epub ahead of print] 112414

Estrogen-mediated inhibition of purine metabolism and cell cycle arrest as a novel therapeutic approach in colorectal cancer.

Batoul Abi Zamer, Jasmin Shafarin, Basma M Sharaf, Hamza M Al Hroub, Nelson C Soares, Mohammad H Semreen, Mawieh Hamad, Jibran Sualeh Muhammad.

  Purine metabolism is upregulated in various cancers including colorectal cancer (CRC). While previous work has elucidated the role of estrogen (E2) in metabolic reprogramming and ATP production, the effect of E2 on purine metabolism remains largely unknown. Herein, the impact of E2 signalling on purine metabolism in CRC cells was investigated using metabolome and transcriptome profiling of cell extracts derived from E2-treated HCT-116 cells with intact or silenced estrogen receptor alpha (ERα). Purine metabolic pathway enrichment analysis showed that 27 genes in the de novo purine synthesis pathway were downregulated in E2-treated CRC cells. Downstream consequences of E2 treatment including the induction of DNA damage, cell cycle arrest, and apoptosis were all shown to be ERα-dependent. These findings demonstrate, for the first time, that E2 exerts a significant anti-growth and survival effect in CRC cells by targeting the purine synthesis pathway in a ERα-dependent manner, meriting further investigation of the therapeutic utility of E2 signalling in CRC.

Keywords:  Colorectal cancer; Estrogen; Metabolomics; Purine metabolism; Transcriptomics

DOI:  https://doi.org/10.1016/j.mce.2024.112414
J Nutr. 2024 Nov 05. pii: S0022-3166(24)01132-5. [Epub ahead of print]

Dietary omega-3 (ω-3) fatty acids mitigate intestinal barrier integrity alterations in mice fed a high-fat diet: Implications for pancreatic carcinogenesis.

Jazmin Machuca, Joanna Wirkus, Aya S Ead, Payam Vahmani, Karen E Matsukuma, Gerardo G Mackenzie, Patricia I Oteiza.

   BACKGROUND: Although body fatness is a recognized risk factor for pancreatic ductal adenocarcinoma (PDAC), the underlying mechanisms of how fat composition affects pancreatic carcinogenesis are poorly understood. High fat diets (HFD) can disrupt intestinal barrier function, potentially accelerating carcinogenesis. Omega-3 (ω-3) polyunsaturated fatty acids (FAs) have anti-inflammatory properties and help preserve intestinal integrity.
OBJECTIVE: to evaluate how ω-3 FAs affect the colonic barrier in the context of HFD-induced changes, in a mouse model of PDAC [p48-Cre; LSL-KrasG12D (KC)].
METHODS: Male and female KC mice were randomized into one of four groups: i) a control diet containing approximately 11% total calories from fat with an ω-6:ω-3 FA ratio of 10:1 (C); ii) the control diet with high levels of ω-3 FA with an ω-6:ω-3 FA ratio of 1:1 (Cω3); iii) a HFD containing 60% total calories from fat with an ω-6:ω-3 FA ratio of approximately 10:1 (HF); iv) a HFD with high levels of ω-3 FA with an ω-6:ω-3 FA ratio of 1:1 (HFω3).
RESULTS: Consumption of a HFD for 8 weeks caused: i) disruption of tight junction structure and function; ii) decreased Goblet cell number, iii) higher colonic TLR4 and NOX1 expression; iv) activation of TLR4-triggered pathways, i.e. NF-κB, JNK1/2; v) elevated plasma LPS levels; v) higher pancreatic TLR4 expression, and vi) accelerated acinar-to-ductal metaplasia. All of these events were mitigated in mice fed the HFω3.
CONCLUSIONS: Our findings support the concept that, in the context of obesity, ω-3 FA have protective effects during early-stage pancreatic carcinogenesis through the regulation of intestinal permeability and endotoxemia.

Keywords:  high fat diet; intestinal permeability; obesity; omega-3 (ω-3) polyunsaturated fatty acids; pancreatic cancer; pancreatic carcinogenesis

DOI:  https://doi.org/10.1016/j.tjnut.2024.10.054
Cell Death Dis. 2024 Nov 14. 15(11): 825

MDM4 inhibits ferroptosis in p53 mutant colon cancer via regulating TRIM21/GPX4 expression.

Jie Liu, Xujin Wei, Yixuan Xie, Yuxiang Yan, Sihui Xue, Xiangyu Wang, Han Chen, Qilong Pan, Sisi Yan, Xiaoling Zheng, Qingling Huang.

MDM4 is one of the major regulators of p53. The biological effect of MDM4 on tumor is controversial, its role and molecular mechanism in colon cancer progression and prognosis are still unclear. In this study, we identify that MDM4 is significantly overexpressed in human colon cancer and high MDM4 expression was associated with poor prognosis of colon cancer with mutant p53. MDM4 inhibits the ubiquitination of the ferroptosis marker protein GPX4 at K167 and K191 by upregulating the protein expression level of the E3 ubiquitin ligase TRIM21, which promotes the polyubiquitination of GPX4 transfer from K48- to K63- linked ubiquitination. Thereby, MDM4 enhances the stability of GPX4 protein, inhibiting ferroptosis, increasing the resistance of colon cancer patients to chemotherapy, and promoting colon cancer progression. These findings elucidate the ferroptosis inhibition effect of MDM4 via regulating TRIM21/GPX4 on p53-mutated colon cancer and provide a potential therapeutic strategy for colon cancer therapy.

DOI: https://doi.org/10.1038/s41419-024-07227-y
Cell Stress Chaperones. 2024 Nov 13. pii: S1355-8145(24)00127-5. [Epub ahead of print]

Protective role of short-chain fatty acids on intestinal oxidative stress induced by TNF-α.

Miguel Ferrer, Berta Buey, Laura Grasa, Jose Emilio Mesonero, Eva Latorre.

  Inflammatory bowel diseases (IBD) are driven by an exaggerated inflammatory response, which leads to a marked increase in oxidative stress. This, in turn, exacerbates the inflammatory process and causes significant cellular and tissue damage. Intestinal dysbiosis, a common observation in IBD patients, alters the production of bacterial metabolites, including short-chain fatty acids (SCFAs), which are key by-products of dietary fiber fermentation. While the role of SCFAs in intestinal physiology is still being elucidated, this study aimed to investigate their effects on intestinal oxidative stress, particularly under inflammatory conditions induced by the proinflammatory mediator tumour necrosis factor alpha (TNF-α). The Caco-2/TC7 cell line was employed as an in vitro model of the intestinal epithelium, and the cells were treated with a range of SCFAs, including acetate, propionate, and butyrate. The levels of protein and lipid oxidation were quantified, as well as the activity of antioxidant enzymes. Our findings demonstrate that microbiota-derived SCFAs can effectively mitigate TNF-α-induced oxidative stress by modulating antioxidant enzyme activity. The proinflammatory mediator TNF-α induces lipid peroxidation by inhibiting catalase and glutathione peroxidase activities. SCFAs are able to upregulate antioxidant enzyme activity to restore lipid oxidative levels. These results underscore the critical role of the gut microbiota in maintaining intestinal homeostasis and highlight the therapeutic potential of SCFAs in managing oxidative stress-related pathologies.

Keywords:  IBD; SCFA; colitis; gut; inflammation

DOI:  https://doi.org/10.1016/j.cstres.2024.11.002
NPJ Precis Oncol. 2024 Nov 09. 8(1): 258

RNF4 mediated degradation of PDHA1 promotes colorectal cancer metabolism and metastasis.

Jierong Chen, Zi-Yue Li, Guansheng Zheng, Lixue Cao, Yun-Miao Guo, Qizhou Lian, Bing Gu, Cai-Feng Yue.

This study investigates the role of RNF4-mediated ubiquitination and degradation of PDHA1 in colorectal cancer (CRC) metabolism and metastasis. Integrating (The Cancer Genome Atlas) TCGA and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, proteomic, clinical, and metabolomic analyses were performed, revealing PDHA1 as a prognostic marker in CRC. Immunohistochemical staining confirmed lower PDHA1 expression in metastatic CRC tissues. In vitro experiments demonstrated that PDHA1 overexpression inhibited CRC cell proliferation, migration, and invasion. RNF4 was identified as a key mediator in the ubiquitination degradation of PDHA1, influencing glycolytic pathways in CRC cells. Metabolomic analysis of serum samples from metastatic CRC patients further supported these findings. In vivo experiments, including xenograft and metastasis models, validated that RNF4 knockdown stabilized PDHA1, inhibiting tumor formation and metastasis. This study highlights the critical role of RNF4-mediated PDHA1 ubiquitination in promoting glycolytic metabolism, proliferation, and metastasis in CRC.

DOI: https://doi.org/10.1038/s41698-024-00724-5
Mol Med Rep. 2025 Jan;pii: 24. [Epub ahead of print]31(1):

KRAS inhibitors may prevent colorectal cancer metachronous metastasis by suppressing TGF‑β mediated epithelial‑mesenchymal transition.

Yaoyu Guo, Chuling Hu, Kuntai Cai, Guojie Long, Du Cai, Zhaoliang Yu, Xinxin Huang, Zerong Cai, Peishan Hu, Yufeng Chen, Feng Gao, Xiaojian Wu.

  In colorectal cancer (CRC), KRAS mutations enhance metachronous metastasis, a condition without prognostic biomarkers or preventive measures. The present study demonstrated that KRAS mutation may be a risk factor for CRC metachronous metastasis through meta‑analysis of public databases. A risk scoring model was constructed using machine learning for predicting metachronous metastasis in KRAS‑mutant CRC. Wound healing and Transwell assay indicated that KRAS inhibitors strongly suppress migration and invasion capabilities of high‑risk CRC cells and these findings were validated through ex vivo organoid and a mouse model of splenic‑liver metastasis. Mechanistically, RNA sequencing, reverse transcription‑quantitative PCR and western blot analyses revealed that KRAS inhibitors suppressed epithelial‑mesenchymal transition (EMT) and transforming growth factor β (TGF‑β) signaling. Notably, addition of TGF‑β1 protein partially reversed the inhibitory effects of KRAS inhibitors on CRC. These results suggested that KRAS inhibitors may prevent CRC metachronous metastasis by downregulating TGF‑β‑mediated EMT, suggesting they can be used prophylactically in high‑risk KRAS‑mutant CRC.

Keywords:  KRAS inhibitor; colorectal cancer; machine learning; metastasis; meta‑analysis

DOI:  https://doi.org/10.3892/mmr.2024.13389