bims-instec 2025-04-27 papers

bims-instec

Biomed News

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

Issue of 2025–04–27
seventeen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer.
Dual states of murine Bmi1-expressing intestinal stem cells drive epithelial development utilizing non-canonical Wnt signaling.
Differential unfolded protein response regulation in KRAS silencing sensitive and innately resistant colorectal cancer cells.
Phospholipase D6 activates Wnt/β-catenin signaling through mitochondrial metabolic reprogramming to promote tumorigenesis in colorectal cancer.
Engineered epithelial curvature controls Paneth cell localization in intestinal organoids.
Multidimensional differences of right- and left-sided colorectal cancer and their impact on targeted therapies.
Non-canonical Wnt co-receptors ROR1/ROR2 are differentially regulated by hypoxia in colon cancer cells.
Asymmetric cell division of ALDH1-positive cancer stem cells generates glycolytic metabolically diverse cell populations.
Proteomics of colorectal tumors identifies the role of CAVIN1 in tumor relapse.
An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer.
MDM2 inhibitor induces apoptosis in colon cancer cells through activation of the CHOP-DR5 pathway, independent of p53 phenotype.
Transcriptome-scale analysis of functional alternative back-splicing events in colorectal cancer.
Geographic and age variations in mutational processes in colorectal cancer.
CD44: A Key Regulator of Iron Metabolism, Redox Balance, and Therapeutic Resistance in Cancer Stem Cells.
METTL1-mediated m7G modification promotes colorectal cancer metastasis via stabilization of ICAM-1.
CDX2 Promoter-Controlled Oncolytic Adenovirus Suppresses Tumor Growth and Liver Metastasis of Colorectal Cancer.
Hypoxic conditions by Raman microspectroscopy - Reprogramming of fatty acids and glucose metabolism during colon cancer progression.

Mol Cancer. 2025 Apr 23. 24(1): 122

LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer.

Christopher A Ladaika, Averi Chakraborty, Ashiq Masood, Galen Hostetter, Joo Mi Yi, Heather M O'Hagan.

   BACKGROUND: BRAF activating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis in part due to an inferior response to standard chemotherapy. Standard of care for patients with refractory metastatic BRAFV600E CRC is treatment with BRAF and EGFR inhibitors and recent FDA approval was given to use these inhibitors in combination with chemotherapy for patients with treatment naïve metastatic BRAFV600E CRC. Lineage plasticity to neuroendocrine cancer is an emerging mechanism of targeted therapy resistance in several cancer types. Enteroendocrine cells (EECs), the neuroendocrine cell of the intestine, are uniquely present in BRAF mutant CRC as compared to BRAF wildtype CRC.
METHODS: BRAF plus EGFR inhibitor treatment induced changes in cell composition were determined by gene expression, imaging and single cell approaches in multiple models of BRAF mutant CRC. Furthermore, multiple clinically relevant inhibitors of the lysine demethylase LSD1 were tested to determine which inhibitor blocked the changes in cell composition.
RESULTS: Combined BRAF and EGFR inhibition enriched for EECs in all BRAF mutant CRC models tested. Additionally, EECs and other secretory cell types were enriched in a subset of BRAFV600E CRC patient samples following targeted therapy. Importantly, inhibition of LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3.
CONCLUSIONS: Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAFV600E CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs. Additionally, our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.

Keywords:  BRAF; Cetuximab; Colorectal cancer; Encorafenib; LSD1; Lineage plasticity; Neuroendocrine

DOI:  https://doi.org/10.1186/s12943-025-02311-z
Dev Cell. 2025 Apr 16. pii: S1534-5807(25)00177-7. [Epub ahead of print]

Dual states of murine Bmi1-expressing intestinal stem cells drive epithelial development utilizing non-canonical Wnt signaling.

Nicholas R Smith, Nicole R Giske, Sidharth K Sengupta, Patrick Conley, John R Swain, Ashvin Nair, Kathryn L Fowler, Christopher Klocke, Yeon Jung Yoo, Ashley N Anderson, Nasim Sanati, Kristof Torkenczy, Andrew C Adey, Jared M Fischer, Guanming Wu, Melissa H Wong.

  Intestinal epithelial development and homeostasis critically rely upon balanced stem cell proliferation, involving slow-cycling/label-retaining and active-cycling/canonical Wnt-dependent intestinal stem cell (ISC) subtypes. ISC regulation during development remains poorly understood but has important implications for establishing key mechanisms governing tissue maintenance. Herein, we identify Bmi1+ cells as functional stem cells present in early murine intestinal development, prior to Lgr5-expressing ISCs. Lineage tracing and single-cell RNA sequencing identify that Bmi1+ ISCs can trace to Lgr5+ ISCs and other differentiated lineages. Initially highly proliferative, Bmi1+ ISCs transition to slow-cycling states as Lgr5+ ISCs emerge. Non-canonical Wnt signaling regulates the proliferative Bmi1+ cell state. These findings highlight the dynamic interplay between stem cell populations and the opposing Wnt pathways that govern proliferation-ultimately having implications for tissue development, homeostasis, regeneration, and tumorigenesis. Understanding these fundamental developmental mechanisms is critical for understanding adult intestinal maintenance.

Keywords:  Bmi1; Wnt signaling; development; intestinal stem cell

DOI:  https://doi.org/10.1016/j.devcel.2025.03.014
Sci Rep. 2025 Apr 24. 15(1): 14329

Differential unfolded protein response regulation in KRAS silencing sensitive and innately resistant colorectal cancer cells.

Flávia Martins, Ana L Machado, Joana Carvalho, Catarina R Almeida, Hans C Beck, Ana S Carvalho, Vadim Backman, Rune Matthiesen, Sérgia Velho.

Despite the development of mutant-selective KRAS inhibitors, colorectal cancer (CRC) responses remain limited, with stable disease and rapid recurrence being common outcomes. The molecular mechanisms enabling CRC cells to tolerate KRAS inhibition and ultimately develop resistance remain poorly understood. Here, we investigated early transcriptional and proteomic responses to KRAS silencing in 3D CRC cell line spheroid models, aiming to identify pathways associated with sensitivity or resistance to KRAS blockade. Cell lines were stratified into KRAS silencing-sensitive (HCT116 and SW480) and -resistant (LS174T and SW837) groups based on spheroid growth, cell cycle progression, and apoptosis induction. Transcriptional profiling revealed the unfolded protein response (UPR) and WNT/β-catenin signaling as pathways specifically upregulated in KRAS silencing-sensitive cells and downregulated in resistant cells. Proteomic analysis of membrane-enriched fractions further supported UPR deregulation, showing a pronounced downregulation of translation-related proteins in sensitive cells. Functional assays validated that the sensitive cell line HCT116 exhibits reduced protein aggregation and lower translational capacity upon KRAS knockdown, consistent with UPR activation. Pharmacological inhibition of IRE1α-mediated UPR signaling did not revert KRAS silencing-induced cell cycle arrest or apoptosis in this cell line. Collectively, our results highlight the UPR activation as an early adaptive response of KRAS-dependent CRC cells to KRAS silencing.

DOI: https://doi.org/10.1038/s41598-025-94549-2
Exp Mol Med. 2025 Apr 21.

Phospholipase D6 activates Wnt/β-catenin signaling through mitochondrial metabolic reprogramming to promote tumorigenesis in colorectal cancer.

Hyun Ji Lee, Seong Hun Lim, Hyesung Lee, Jung Min Han, Do Sik Min.

Phospholipase D6 (PLD6) is a critical enzyme involved in mitochondrial fusion with a key role in spermatogenesis. However, the role of PLD6 in cancer remains unknown. Notably, Wnt signaling, energy metabolism and mitochondrial function show complex interactions in colorectal cancer (CRC) progression. Here we found that PLD6 is highly expressed in CRC and positively correlated with poor prognosis. We present a novel function of PLD6 in activating Wnt/β-catenin signaling by enhancing mitochondrial metabolism. PLD6 depletion suppresses the oncogenic properties of CRC cells and impairs mitochondrial respiration, leading to reduced mitochondrial length, membrane potential, calcium levels and reactive oxygen species. PLD6 depletion also disrupts mitochondrial metabolic reprogramming by inhibiting the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation, resulting in altered intracellular levels of citrate and acetyl-CoA-both key modulators of Wnt/β-catenin activation. PLD6-mediated acetyl-CoA production enhances β-catenin stability by promoting its acetylation via the acetyltransferases CREB-binding protein and P300/CREB-binding-protein-associated factor. Consequently, PLD6 ablation reduces cancer stem cell-associated gene expression downstream of Wnt/β-catenin signaling, suppressing stem-like traits and chemoresistance to 5-fluorouracil. Furthermore, PLD6 depletion attenuates CRC tumorigenesis in both subcutaneous and orthotopic tumor models. Overall, PLD6 acts as an oncogenic switch by promoting mitochondria-mediated retrograde signaling, thereby regulating Wnt signaling in CRC.

DOI: https://doi.org/10.1038/s12276-025-01446-9
Cell Biomater. 2025 Apr 22. pii: 100046. [Epub ahead of print]1(3):

Engineered epithelial curvature controls Paneth cell localization in intestinal organoids.

F Max Yavitt, Alex Khang, Kaustav Bera, Delaney L McNally, Michael R Blatchley, Aaron P Gallagher, Ophir D Klein, David Castillo-Azofeifa, Peter J Dempsey, Kristi S Anseth.

The cellular organization within organoid models is important to regulate tissue specific function, yet few engineering approaches can control or direct cellular organization. Here, a photodegradable hydrogel is used to create softened regions that direct crypt formation within intestinal organoids, where the dimensions of the photosoftened regions generate predictable and defined crypt architectures. Guided by in vivo metrics of crypt morphology, this photopatterning method is used to control the width and length of in vitro organoid crypts, which ultimately defines the curvature of the epithelium. By tracking expression of differentiated Paneth cell markers in real-time, we show that epithelial curvature directs the localization of Paneth cells within engineered crypts, providing user-directed control over organoid functionality. We anticipate that our improved control over organoid architecture and thus Paneth cell localization will lead to more consistent in vitro organoid models for both mechanistic studies and translational applications.

DOI: https://doi.org/10.1016/j.celbio.2025.100046
NPJ Precis Oncol. 2025 Apr 22. 9(1): 116

Multidimensional differences of right- and left-sided colorectal cancer and their impact on targeted therapies.

Marwa Abdel Hamid, Lorenz M Pammer, Silvia Oberparleiter, Michael Günther, Arno Amann, Rebecca A Gruber, Anna Mair, Fabienne I Nocera, Steffen Ormanns, Kai Zimmer, Romana R Gerner, Florian Kocher, Samuel M Vorbach, Dominik Wolf, Jakob M Riedl, Florian Huemer, Andreas Seeber.

Despite advances in metastatic colorectal cancer (mCRC) treatment, long-term survival remains poor, particularly in right-sided colorectal cancer (RCRC), which has a worse prognosis compared to left-sided CRC (LCRC). This disparity is driven by the complex biological diversity of these malignancies. RCRC and LCRC differ not only in clinical presentation and outcomes but also in their underlying molecular and genetic profiles. This article offers a detailed literature review focusing on the distinctions between RCRC and LCRC. We explore key differences across embryology, anatomy, pathology, omics, and the tumor microenvironment (TME), providing insights into how these factors contribute to prognosis and therapeutic responses. Furthermore, we examine the therapeutic implications of these differences, considering whether the conventional classification of CRC into right- and left-sided forms should be refined. Recent molecular findings suggest that this binary classification may overlook critical biological complexities. Therefore, we propose that future approaches should integrate molecular insights to better guide personalized treatments, especially anti-EGFR therapies, and improve patient outcomes.

DOI: https://doi.org/10.1038/s41698-025-00892-y
Biochim Biophys Acta Mol Cell Res. 2025 Apr 21. pii: S0167-4889(25)00073-4. [Epub ahead of print]1872(5): 119968

Non-canonical Wnt co-receptors ROR1/ROR2 are differentially regulated by hypoxia in colon cancer cells.

Eduardo Alvarado-Ortiz, María Cristina Castañeda-Patlán, Angela Patricia Moreno-Londoño, José Manuel Tinajero-Rodríguez, Paola Briseño-Díaz, Miguel Angel Sarabia-Sánchez, Miguel Vargas, Elizabeth Ortiz-Sánchez, Martha Robles-Flores.

  ROR1 and ROR2 co-receptors are transducers of non-canonical Wnt responses that promote an aggressive phenotype in several cancer types, including colon cancer. It has been demonstrated that hypoxia promotes tumor progression through the action of Hypoxia Inducible Factors (HIFs). An in silico analysis revealed that ROR2 is overexpressed in the advanced clinical stages of colon cancer. In line with this, ROR1 and ROR2 were found to be only expressed in malignant colon cells compared to non-malignant ones. The blockade of either ROR1 or ROR2 impaired colon cancer cells' colony formation abilities and the migration capacity of them. Additionally, the silencing of the ROR2 co-receptor blocked the metastatic ability of colon cancer cells in a xenografted mice model. We found that while silencing HIF-1α did not significantly reduce ROR1 or ROR2 expression, inhibiting HIF-2α and HIF-3α expression greatly decreased the protein levels of both co-receptors in colon cancer cells. The HIF-1α subunit expression is induced in acute hypoxia, whereas HIF-2α and HIF-3α show higher activity in chronic hypoxia, which may be functionally relevant since hypoxia induced a decrease in the constitutive active β-catenin transcriptional activity in SW480 cells. While both ROR1 and ROR2 stimulate proliferation and migration under normoxic conditions, the exposure of cells to hypoxia increased the expression of ROR1 or ROR2, depending on the Wnt cellular context, Thus, our results indicate that hypoxia partially represses β-catenin transcriptional activity and activates non-canonical Wnt signaling by regulating ROR1/ROR2 expression to induce an aggressive migrating and metastatic phenotype in colon cancer cells.

Keywords:  Hypoxia; Hypoxia inducible factors; Metastasis; Non-canonical Wnt signaling; ROR1/ROR2 co-receptors

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119968
Sci Rep. 2025 Apr 22. 15(1): 13932

Asymmetric cell division of ALDH1-positive cancer stem cells generates glycolytic metabolically diverse cell populations.

Shoma Tamori, Chika Matsuda, Takahiro Kasai, Shigeo Ohno, Kazunori Sasaki, Kazunori Akimoto.

Metabolic heterogeneity in various cancer cells within a tumor causes resistance to medical therapies and promotes tumor recurrence and metastasis. However, the mechanisms by which tumors acquire metabolic heterogeneity are poorly understood. Here, we revealed that PKCλ-dependent asymmetric division of ALDH1-positive cancer stem cells (CSCs) led to an uneven distribution of glycolytic capacity, which is crucial for understanding metabolic heterogeneity within a tumor. The rate-limiting enzyme PFKP and the metabolic probe CDG in glycolysis codistributed with the ALDH1A3 protein during the post-cell division phase, highlighting a mechanism for acquiring metabolic diversity. PKCλ deficiency reduced the asymmetric distribution of these proteins in ALDH1high cells with high ALDH1 activity, suggesting a fundamental role for PKCλ in metabolic heterogeneity. We identified 28 distinct distribution patterns combining PFKP and CDG distributions, demonstrating the complexity of glycolytic heterogeneity. Furthermore, validation and prediction of cell distribution patterns via a probabilistic model confirmed that PKCλ deficiency diminished glycolytic diversity in individual cells within a cancer cell colony generated from an ALDH1-positive CSC. These findings suggest that PKCλ-dependent asymmetric cell division of ALDH1-positive CSCs is crucial for glycolytic heterogeneity in cancer cells within a tumor, potentially offering new therapeutic targets against tumor resistance and metastasis.

DOI: https://doi.org/10.1038/s41598-025-97985-2
Mol Syst Biol. 2025 Apr 23.

Proteomics of colorectal tumors identifies the role of CAVIN1 in tumor relapse.

Ana Martinez-Val, Leander Van der Hoeven, Dorte B Bekker-Jensen, Margarita Melnikova Jørgensen, Jesper Nors, Giulia Franciosa, Claus L Andersen, Jesper B Bramsen, Jesper V Olsen.

  Colorectal cancer molecular signatures derived from omics data can be employed to stratify CRC patients and aid decisions about therapies or evaluate prognostic outcome. However, molecular biomarkers for identification of patients at increased risk of disease relapse are currently lacking. Here, we present a comprehensive multi-omics analysis of a Danish colorectal cancer tumor cohort composed of 412 biopsies from tumors of 371 patients diagnosed at TNM stage II or III. From mass spectrometry-based patient proteome profiles, we classified the tumors into four molecular subtypes, including a mesenchymal-like subtype. As the mesenchymal-rich tumors are known to represent the most invasive and metastatic phenotype, we focused on the protein signature defining this subtype to evaluate their potential as relapse risk markers. Among signature-specific proteins, we followed-up Caveolae-Associated Protein-1 (CAVIN1) and demonstrated its role in tumor progression in a 3D in vitro model of colorectal cancer. Compared to previous omics analyses of CRC, our multi-omics classification provided deeper insights into EMT in cancer cells with stronger correlations with risk of relapse.

Keywords:  CAVIN1; Colorectal Cancer; Proteomics; Tumor Relapse

DOI:  https://doi.org/10.1038/s44320-025-00102-8
Nat Nanotechnol. 2025 Apr 23.

An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer.

Kai Zhao, Yu Yan, Xiao-Kang Jin, Ting Pan, Shi-Man Zhang, Chi-Hui Yang, Zhi-Yong Rao, Xian-Zheng Zhang.

Chemoresistance and immunosuppression are common obstacles to the efficacy of chemo-immunotherapy in colorectal cancer (CRC) and are regulated by mitochondrial chaperone proteins. Here we show that the disruption of the tumour necrosis factor receptor-associated protein 1 (TRAP1) gene, which encodes a mitochondrial chaperone in tumour cells, causes the translocation of cyclophilin D in tumour cells. This process results in the continuous opening of the mitochondrial permeability transition pore, which enhances chemotherapy-induced cell necrosis and promotes immune responses. On the basis of this discovery we developed an oral CRISPR-Cas9 delivery system based on zwitterionic and polysaccharide polymer-coated nanocomplexes that disrupts the TRAP1 gene in CRC. This system penetrates the intestinal mucus layer and undergoes epithelial transcytosis, accumulating in CRC tissues. It enhances chemotherapeutic efficacy by overcoming chemoresistance and activating the tumour immune microenvironment in orthotopic, chemoresistant and spontaneous CRC models, with remarkable synergistic antitumour effects. This oral CRISPR-Cas9 delivery system represents a promising therapeutic strategy for the clinical management of CRC.

DOI: https://doi.org/10.1038/s41565-025-01904-5
Front Pharmacol. 2025 ;16 1508421

MDM2 inhibitor induces apoptosis in colon cancer cells through activation of the CHOP-DR5 pathway, independent of p53 phenotype.

Manman Lu, Yingli Ren, Sijia Feng, Shenggen Wang, Weiyue Xia, Baoru Gu, Yuhou Shen, Aimin Yue, Na Li, Yongxi Zhang, Jiateng Zhong.

   Introduction: Murine double minute 2 (MDM2), a key negative regulator of p53, forms a feedback loop with p53 to drive tumor progression, including colorectal cancer. Nutlin-3a, an MDM2 inhibitor, induces apoptosis in wild-type p53 tumors, but its effects on p53-mutated cancers and potential p53-independent apoptotic mechanisms remain unclear.
Methods: We investigated Nutlin-3a's effects on colon cancer cells with varying p53 phenotypes. Endoplasmic reticulum (ER) stress-associated CHOP was detected and knocked down to explore mechanisms. In vitro and in vivo experiments assessed Nutlin-3a's synergy with 5-fluorouracil and TRAIL.
Results: Nutlin-3a activated caspase-8-dependent extrinsic apoptosis in colon cancer cells via DR5 upregulation, independent of p53 status. ER stress and CHOP activation mediated DR5 induction, driven by calcium release. Combined Nutlin-3a treatment enhanced sensitivity to 5-fluorouracil and TRAIL in vitro and in vivo through caspase-8 pathway activation.
Discussion: These findings reveal a novel p53-independent apoptotic mechanism of Nutlin-3a involving ER stress and death receptor signaling. This pathway highlights Nutlin-3a's potential as an adjuvant therapy for colon cancer, even in p53-mutated tumors, by enhancing chemotherapeutic efficacy through extrinsic apoptosis.

Keywords:  ER stress; apoptosis; colorectal cancer; extrinsic apoptotic pathway; nutlin-3a

DOI:  https://doi.org/10.3389/fphar.2025.1508421
J Transl Med. 2025 Apr 24. 23(1): 468

Transcriptome-scale analysis of functional alternative back-splicing events in colorectal cancer.

Qianqian Ning, Qian Jin, Lei Zhao, Yudi Wang, Jie Wang, Lili Yang, Ye Han, Qiaoming Zhi, Junnian Zheng, Feifei Chen, Dong Dong.

   BACKGROUND: Circular RNAs (circRNAs) are a class of non-polyadenylated RNAs generated from back-splicing of genes. Multiple circRNAs can be generated at a single gene locus through alternative back-splicing events (ABS), sharing the same 5' or 3' back-splice site. To date, how prevalent ABS events are and how they are participated in carcinogenesis of human colorectal cancer (CRC) remains unexplored.
METHODS: To explore the functional roles of ABS events in CRC carcinogenesis, we analyzed ribosomal RNA-depleted transcriptome sequencing data of 176 CRC samples and characterized the landscape of ABS events in CRC. CRC cancer-related ABS events were identified by comparing paired CRC tumor tissues and adjacent normal tissues. Then, univariate and multivariate Cox regression was used to find prognostic ABS events. Moreover, in vitro and in vivo assays were used to exploring the functional roles of circXPO1-1 and circXPO1-2 in CRC.
RESULTS: We totally identified 19,611 high confidence circRNAs in CRC, among which 17,874 (91·1%) of circRNAs were found recurrently. The number of ABS circRNAs accounted for 68.8% of all identified high confidence circRNAs, which suggested that ABS events are prevalent in CRC transcriptome. Particularly, 552 ABS circRNAs were found to be aberrantly expressed between paired CRC tumor tissues and adjacent normal tissues, and their parent genes are closely associated with cancer-related hallmarks. In addition, 13 differential ABS circRNAs were identified to be associated with CRC patient survival and could act as independent prognostic indicators. Furthermore, we identified two ABS circRNAs of XPO1 gene (circXPO1-1 and circXPO1-2). The result showed that overexpression of circXPO1-2 inhibited CRC cell proliferation, migration, and invasion in vitro and in vivo, whereas circXPO1-1 is not, indicating that the circularization isoforms of XPO1 gene have different functions in CRC.
CONCLUSIONS: In conclusion, our work provides the landscape of ABS events in CRC transcriptome and the close association of ABS circRNAs with tumorigenesis offers a new set of targets with potential clinical benefit.

Keywords:  Alternative back-splicing event; CircXPO1; Circular RNA; Colorectal cancer

DOI:  https://doi.org/10.1186/s12967-025-06479-2
Nature. 2025 Apr 23.

Geographic and age variations in mutational processes in colorectal cancer.

Marcos Díaz-Gay, Wellington Dos Santos, Sarah Moody, Mariya Kazachkova, Ammal Abbasi, Christopher D Steele, Raviteja Vangara, Sergey Senkin, Jingwei Wang, Stephen Fitzgerald, Erik N Bergstrom, Azhar Khandekar, Burçak Otlu, Behnoush Abedi-Ardekani, Ana Carolina de Carvalho, Thomas Cattiaux, Ricardo Cortez Cardoso Penha, Valérie Gaborieau, Priscilia Chopard, Christine Carreira, Saamin Cheema, Calli Latimer, Jon W Teague, Anush Mukeriya, David Zaridze, Riley Cox, Monique Albert, Larry Phouthavongsy, Steven Gallinger, Reza Malekzadeh, Ahmadreza Niavarani, Marko Miladinov, Katarina Erić, Sasa Milosavljevic, Suleeporn Sangrajrang, Maria Paula Curado, Samuel Aguiar, Rui Manuel Reis, Monise Tadin Reis, Luis Gustavo Romagnolo, Denise Peixoto Guimarães, Ivana Holcatova, Jaroslav Kalvach, Carlos Alberto Vaccaro, Tamara Alejandra Piñero, Beata Świątkowska, Jolanta Lissowska, Katarzyna Roszkowska-Purska, Antonio Huertas-Salgado, Tatsuhiro Shibata, Satoshi Shiba, Surasak Sangkhathat, Taned Chitapanarux, Gholamreza Roshandel, Patricia Ashton-Prolla, Daniel C Damin, Francine Hehn de Oliveira, Laura Humphreys, Trevor D Lawley, Sandra Perdomo, Michael R Stratton, Paul Brennan, Ludmil B Alexandrov.

Colorectal cancer incidence rates vary geographically and have changed over time1. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries2-5. The reasons for this increase are unknown. Here, we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown etiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia, and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin6,7, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals diagnosed before age 40 than in those over 70, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer.

DOI: https://doi.org/10.1038/s41586-025-09025-8
Stem Cells. 2025 Apr 22. pii: sxaf024. [Epub ahead of print]

CD44: A Key Regulator of Iron Metabolism, Redox Balance, and Therapeutic Resistance in Cancer Stem Cells.

Taiju Ando, Juntaro Yamasaki, Hideyuki Saya, Osamu Nagano.

  CD44, a multifunctional cell surface protein, has emerged as a pivotal regulator in cancer stem cell (CSC) biology, orchestrating processes such as stemness, metabolic reprogramming, and therapeutic resistance. Recent studies have identified a critical role of CD44 in ferroptosis resistance by stabilizing SLC7A11 (xCT), a key component of the antioxidant defense system, enabling CSCs to evade oxidative stress and sustain tumorigenic potential. Additionally, CD44 regulates intracellular iron metabolism and redox balance, further supporting CSC survival and adaptation to stressful microenvironments. Therapeutic strategies targeting CD44, including ferroptosis inducers and combination therapies, have shown significant potential in preclinical and early clinical settings. Innovations such as CD44-mediated nanocarriers and metabolic inhibitors present novel opportunities to disrupt CSC-associated resistance mechanisms. Furthermore, the dynamic plasticity of CD44 isoforms governed by transcriptional, post-transcriptional, and epigenetic regulation underscores the importance of context-specific therapeutic approaches. This review highlights the multifaceted roles of CD44 in CSC biology, focusing on its contribution to ferroptosis resistance, iron metabolism, and redox regulation. Targeting CD44 offers a promising avenue for overcoming therapeutic resistance and improving the outcomes of refractory cancers. Future studies are needed to refine these strategies and enable their clinical translation.

Keywords:  CD44; Cancer stem cell; Ferroptosis; Iron metabolism; SLC7A11

DOI:  https://doi.org/10.1093/stmcls/sxaf024
Mol Cell Biochem. 2025 Apr 19.

METTL1-mediated m7G modification promotes colorectal cancer metastasis via stabilization of ICAM-1.

Shangwen Cai, Shuyi Mi, Jingyu Chen, Liming Shao, Xiaoyun Yang, Meng Xue.

  Colorectal cancer (CRC) is one of the most common tumors worldwide, and metastatic CRC is likely to have a poor prognosis. N7-methylguanosine (m7G) is a common methylation modification that is catalyzed primarily by methyltransferase 1 (METTL1). However, the role of m7G in metastatic CRC remains unclear. The role of METTL1 in progressive CRC was initially explored using bioinformatics analysis. Subsequently, its relationship with CRC was further validated through in vitro and in vivo experiments. Potential downstream targets were identified through RNA-seq and quantitative real-time PCR (RT‒qPCR), and the underlying mechanisms were investigated using methylated RNA immunoprecipitation (MeRIP) and RNA degradation assays. Our results revealed that METTL1 is differentially expressed and significantly upregulated in metastatic CRC. This correlation was further confirmed by in vivo and in vitro experiments. RNA sequencing of CRC cells with METTL1 knockdown revealed that intercellular adhesion molecule-1 (ICAM-1) was a significant downstream target and could be stabilized by m7G modification. We revealed that METTL1 is significantly upregulated in metastatic CRC and plays a critical role in CRC progression by stabilizing ICAM-1 through m7G modification.

Keywords:  Colorectal cancer (CRC); Intercellular adhesion molecule-1 (ICAM-1); Metastasis; Methyltransferase1 (METTL1); N7-methylguanosine (m7G)

DOI:  https://doi.org/10.1007/s11010-025-05293-0
Cancer Sci. 2025 Apr 24.

CDX2 Promoter-Controlled Oncolytic Adenovirus Suppresses Tumor Growth and Liver Metastasis of Colorectal Cancer.

Naohiko Nakamura, Mizuho Sato-Dahlman, Elise Travis, Kari Jacobsen, Masato Yamamoto.

  Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, and liver metastasis (CRLM) is the most common among its distant metastases. We have recently generated a CDX2 promoter-controlled oncolytic adenovirus (Ad5/3-pCDX2) that showed an anticancer effect for CDX2-positive upper gastrointestinal tumors. Here, we reported the anticancer effect of Ad5/3-pCDX2 for CDX2-positive CRC and CRLM, and its combination efficacy with 5-fluorouracil (5FU) in vitro and in vivo. We used HT29 as CDX2-positive, and LS174T and SW480 as CDX2-negative CRC cell lines. Without 5FU, Ad5/3-pCDX2 killed HT29 but not LS174T and SW480 cells. In vitro, 5FU exposure upregulated CDX2 mRNA levels in all three cell lines. The 5FU combination enhanced the cytocidal effect and virus replication of Ad5/3-pCDX2 in CDX2-negative LS174T. In mouse xenograft models, Ad5/3-pCDX2 monotherapy suppressed the HT29 subcutaneous tumor growth compared to the control group. The 5FU plus Ad5/3-pCDX2 combination therapy showed a remarkable antitumor effect over the efficacy of Ad5/3-pCDX2 monotherapy. In the LS174T subcutaneous tumor, although Ad5/3-pCDX2 monotherapy did not show an antitumor effect, the 5FU plus Ad5/3-pCDX2 combination therapy significantly suppressed the tumor growth compared to the Ad5/3-pCDX2 monotherapy. In mice with HT29 liver metastasis, intrasplenic injection of Ad5/3-pCDX2 induced virus replication in liver tumors and thus successfully attenuated tumor growth. In conclusion, Ad5/3-pCDX2 showed a significant anticancer effect that was enhanced by 5FU treatment in not only CDX2-positive but also negative CRCs. Ad5/3-pCDX2 is a promising therapeutic modality for metastatic CRC such as CRLM.

Keywords:  CDX2; chemotherapy; colorectal cancer; liver metastasis; oncolytic adenovirus

DOI:  https://doi.org/10.1111/cas.70063
Spectrochim Acta A Mol Biomol Spectrosc. 2025 Apr 19. pii: S1386-1425(25)00581-5. [Epub ahead of print]339 126275

Hypoxic conditions by Raman microspectroscopy - Reprogramming of fatty acids and glucose metabolism during colon cancer progression.

Monika Kopeć, Karolina Beton-Mysur, Jakub Surmacki, Beata Brożek-Płuska.

  Cellular respiration is the primary metabolic process for producing the energy (ATP) needed for survival. Disruptions in this process can lead to various diseases, including colon cancer. This paper reviews the current understanding of how excess fatty acids (FAs) and glucose (Glc) alter metabolic pathways. We focused on the impact of unsaturated fatty acids (UFAs) (eicosapentaenoic acid (EPA), linoleic acid (LA)), saturated fatty acid (SFA) (palmitic acid (PA)), and glucose on healthy human colon cells (CCD-18 Co) and cancerous colon cells (Caco-2) using Raman microspectroscopy. Our study examined the metabolic abnormalities in mitochondria and lipid droplets caused by the external intake of FAs and glucose. The results indicate that the peaks at 750 cm-1, 1004 cm-1, 1256 cm-1, 1444 cm-1, and 1656 cm-1 can serve as Raman biomarkers for monitoring metabolic pathways in colon cancer. We proved that oxidative metabolism towards glycolysis allows maintaining redox homeostasis and enables the survival and proliferation of cancer cells in hypoxic conditions. Our findings show that comparing control cells with cells supplemented with UFAs, SFA, and glucose can help detect metabolic abnormalities. Specifically, supplementation with UFAs reduces the intensity of the bands at 750 cm-1 and 1004 cm-1, while SFA and glucose increase their intensity. For the bands at 1256 cm-1, 1444 cm-1, and 1656 cm-1, palmitic acid and glucose decrease the intensity, whereas linoleic acid increases it. This paper introduces new experimental techniques, such as Raman microspectroscopy and imaging, to track and understand the metabolic changes in colon cells caused by FAs and glucose under hypoxic conditions.

Keywords:  Colon cancer biomarkers; Fatty acids; Glucose; Hypoxia; Raman microspectroscopy

DOI:  https://doi.org/10.1016/j.saa.2025.126275