bims-instec 2025-09-07 papers

bims-instec

Biomed News

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

Issue of 2025–09–07
twenty-six papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Epithelial tension controls intestinal cell extrusion.
NOX1 and NPY1R mark regional colon stem cell populations that serve as cancer origins in vivo.
ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.
Lipid Composition Alters Ferroptosis Sensitivity.
SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer.
CLK2 Regulates the KEAP1/NRF2 and p53 Pathways to Suppress Ferroptosis in Colorectal Cancer.
FASN promotes the stemness of cancer stem cells and protects colorectal cancer cells from ferroptosis by inhibiting the activation of SREBP2.
C20orf27 regulates colorectal cancer growth and metastasis based on different lipid levels.
Organoids as models of immune-organ interaction.
Epigenomics and CRISPRi reveal cis-regulatory elements in colorectal cancer.
Loss of WNT2B Increases Progression from Dysplasia to Colorectal Cancer.
Primary tumor sidedness and negative hyperselection to modulate anti-EGFR-based maintenance strategies in patients with RAS wild-type metastatic colorectal cancer: individual patient data pooled analysis of two randomized clinical trials.
Rapid activation of ARF6 after RAF inhibition augments BRAFV600E and promotes therapy resistance.
Novel organoid culture condition: modeling fetal-like plasticity in colorectal cancer.
Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer.
FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.
ACTL6A depletion induces KLF4-mediated anti-tumorigenic effects in colorectal cancer.
Metabolic Plasticity and Cancer Stem Cell Metabolism: Exploring the Glycolysis-OXPHOS Switch as a Mechanism for Resistance and Tumorigenesis.
HADHB mediates 5-fluorouracil sensitivity in colorectal cancer.
Gut microbiota dysbiosis affects intestinal sensitivity through epithelium-to-neuron signaling: novel insights from a colon organoid-based model to improve visceral pain therapy.
Intestinal catabolism of dietary fructose promotes obesity and insulin resistance via ileal lacteal remodeling.
A single-cell atlas of transcriptome changes in the intestinal epithelium at the suckling-to-weaning transition in male rabbits.
Addendum: Retinoic acid signaling is critical during the totipotency window in early mammalian development.
Machine learning integration of bulk and single-cell RNA-seq data reveals glycolytic heterogeneity in colorectal cancer.
Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse.
FSP1 reduces exogenous coenzyme Q10 and inhibits ferroptosis to alleviate intestinal ischemia-reperfusion injury.

Science. 2025 Sep 04. 389(6764): eadr8753

Epithelial tension controls intestinal cell extrusion.

Daniel Krueger, Willem Kasper Spoelstra, Dirk Jan Mastebroek, Rutger N U Kok, Shanie Wu, Mike Nikolaev, Marie Bannier-Hélaouët, Nikolche Gjorevski, Matthias Lutolf, Johan van Es, Jeroen van Zon, Sander J Tans, Hans Clevers.

Cell extrusion is essential for homeostatic self-renewal of the intestinal epithelium. Extrusion is thought to be triggered by crowding-induced compression of cells at the intestinal villus tip. In this study, we found instead that a local "tug-of-war" competition between contractile cells regulated extrusion in the intestinal epithelium. We combined quantitative live microscopy, optogenetic induction of tissue tension, genetic perturbation of myosin II activity, and local disruption of the basal cortex in mouse intestines and intestinal organoids. These approaches revealed that a dynamic actomyosin network generates tension throughout the intestinal villi, including the villus tip region. Mechanically weak cells unable to maintain this tension underwent extrusion. Thus, epithelial barrier integrity depends on intercellular mechanics.

DOI: https://doi.org/10.1126/science.adr8753
Nat Cell Biol. 2025 Sep 02.

NOX1 and NPY1R mark regional colon stem cell populations that serve as cancer origins in vivo.

Maxime Gasnier, Tanysha Chi-Ying Chen, Swathi Yada, Sowmya Sagiraju, Yusuke Yoshikawa, Stefano Perna, Hui Yi Grace Lim, Bernett Lee, Nick Barker.

Current colorectal cancer mouse models either lack colon specificity, limiting progression towards more advanced disease, or preclude evaluation of resident stem cells as cancer origins. Here we report the identification of NOX1 and NPY1R as cell-surface markers enriched in LGR5+ stem cells predominantly within the caecum and exclusively within the middle and distal colorectum, respectively. Selective dysregulation of Wnt signalling in NOX1+ or NPY1R+ stem cells using CreERT2 mouse lines drives colon cancer initiation, predominantly within the caecum and rectum respectively, establishing these stem cell populations as important sources of colon cancer. Selective conditional activation of Wnt signalling and oncogenic Kras in combination with loss of TRP53 in these stem cell compartments resulted in the development of advanced, invasive cancers. This study establishes CreERT2 drivers as valuable tools for studying stem cell contributions to colon cancer.

DOI: https://doi.org/10.1038/s41556-025-01763-1
Nat Metab. 2025 Sep 01.

ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.

Olivia I Coleman, Adam Sorbie, Alessandra Riva, Miriam von Stern, Stephanie Kuhls, Denise M Selegato, Luisa Siegert, Isabel Keidel, Nikolai Köhler, Jakob Wirbel, Tim Kacprowski, Andreas Dunkel, Josch K Pauling, Johannes Plagge, Diego Mediel-Cuadra, Sophia J Wagner, Ines Chadly, Sandra Bierwith, Tingying Peng, Thomas Metzler, Xin Li, Mathias Heikenwälder, Clemens Schafmayer, Sebastian Hinz, Christian Röder, Christoph Röcken, Michael Zimmermann, Philip Rosenstiel, Katja Steiger, Moritz Jesinghaus, Gerhard Liebisch, Josef Ecker, Christina Schmidt, Georg Zeller, Klaus-Peter Janssen, Dirk Haller.

Endoplasmic reticulum unfolded protein responses contribute to cancer development, with activating transcription factor 6 (ATF6) involved in microbiota-dependent tumorigenesis. Here we show the clinical relevance of ATF6 in individuals with early-onset and late colorectal cancer, and link ATF6 signalling to changes in lipid metabolism and intestinal microbiota. Transcriptional analysis in intestinal epithelial cells of ATF6 transgenic mice (nATF6IEC) identifies bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype labelling confirm ATF6-related enrichment of long-chain fatty acids in colonic tissue of humans, mice and organoids. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirm the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumour-relevant microbial taxa, including Desulfovibrio fairfieldensis, is mechanistically linked to long-chain fatty acid exposure using bioorthogonal non-canonical amino acid tagging, and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signalling to select for tumour-promoting microbiota by altering lipid metabolism.

DOI: https://doi.org/10.1038/s42255-025-01350-6
Cancer Res. 2025 Sep 05.

Lipid Composition Alters Ferroptosis Sensitivity.

Vivian S Park, Lauren E Pope, Justin P Ingram, Grace A Alchemy, Julie J Purkal, Magdalena B Murray, Sha Jin, Eli Y Andino-Frydman, Sanjana Singh, Anlu Chen, Priya Narayanan, Sarah Kongpachith, Darren C Phillips, Scott J Dixon, Relja Popovic.

Ferroptosis is a regulated non-apoptotic cell death process characterized by iron-dependent lipid peroxidation. Peroxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) is necessary for the execution of ferroptosis. Glutathione peroxidase 4 (GPX4) suppresses ferroptosis by reducing lipid hydroperoxides to lipid alcohols. GPX4 may be a useful target for drug development, highlighting the need to identify factors that govern GPX4 inhibitor sensitivity. Here, we found that reduced GPX4 expression was sufficient to induce ferroptosis in multiple adherent (2D) cancer cell cultures. However, lower GPX4 protein levels did not consistently affect tumor xenograft growth in mice. Culturing cells as spheroids (3D) was sufficient to reduce sensitivity to pharmacological GPX4 inhibition. Mechanistically, growth in 3D versus 2D conditions upregulated expression of the monounsaturated fatty acid (MUFA) biosynthetic gene stearoyl-CoA desaturase (SCD), altering the ratio of MUFA-PLs to PUFA-PLs in a direction favoring ferroptosis resistance. Similar shifts in MUFA-PL to PUFA-PL ratios were observed in xenograft tumors. Thus, lipidome remodeling in 3D growth conditions and in vivo may limit GPX4 inhibitor efficacy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4207
Cell Rep. 2025 Sep 01. pii: S2211-1247(25)00910-6. [Epub ahead of print]44(9): 116139

SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer.

Xiaojun Zhou, Genxin Wang, Yuhang Wu, Mingzhi Wu, Xiang Zhai, Chenhui Tian, Edward V Prochownik, Congqing Jiang, Youjun Li.

  Tumor metabolic reprogramming is critical for providing energy to support proliferation and resistance to stress-induced cell death. However, the regulatory mechanisms linking these processes remain incompletely understood. Here, using untargeted metabolomics, we demonstrate that creatine potently induces ferroptosis in colorectal cancer (CRC). Mechanistically, creatine binds extracellular signal-regulated kinase 2 (ERK2), impairing its activation by mitogen-activated protein kinase kinase 1 (MEK1). Inhibiting the creatine transporter SLC6A8 reduces creatine uptake and activates ERK2. Activated ERK2 then binds, phosphorylates ferroptosis suppressor protein 1 (FSP1) at Thr109, and stabilizes it to inhibit ferroptosis. Creatine supplementation suppresses tumor growth, enhances CD8+ T cell infiltration, and sensitizes tumors to anti-programmed cell death protein 1 (PD-1) immunotherapy. Our study identifies ERK2 as a creatine sensor regulating FSP1 stability and ferroptosis resistance, highlighting the therapeutic potential of creatine supplementation in combination cancer immunotherapy.

Keywords:  CP: Cancer; CP: Metabolism; creatine; ferroptosis; mmune checkpoint blockade; tumor metabolic reprogramming

DOI:  https://doi.org/10.1016/j.celrep.2025.116139
Cancer Res. 2025 Aug 29.

CLK2 Regulates the KEAP1/NRF2 and p53 Pathways to Suppress Ferroptosis in Colorectal Cancer.

Hai-Meng Zhou, Yi Liu, Feng Shi, Hao-Wen Qiu, Le Li, Qi-Peng Shu, Yu-Ying Liu, Bai-Qi Wang, Meng Gao, Run-Lei Du, Shao-Bo Ke, Xiao-Dong Zhang.

Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, plays a crucial role in colorectal cancer (CRC) progression and therapeutic response. The NRF2 pathway is one of the critical axes in ferroptosis regulation, which governs oxidative stress resistance and iron homeostasis through its downstream targets, including HMOX1, SLC7A11, and others. However, HMOX1 and SLC7A11 exhibit contrasting roles in ferroptosis, with HMOX1 promoting ferroptosis via iron accumulation and lipid peroxidation, while SLC7A11 inhibits ferroptosis by enhancing antioxidant defenses. Here, we identified CLK2 as a key regulator of the delicate balance of the opposing effects of HMOX1 and SLC7A11. CLK2 stabilized KEAP1 to suppress NRF2 activity, resulting in the downregulation of HMOX1 and SLC7A11. Simultaneously, CLK2 downregulated p53, thereby relieving p53-mediated repression of SLC7A11. The dual regulation by CLK2 disrupted the balance between HMOX1 and SLC7A11, leading to excessive activation of HMOX1 in the absence of CLK2, ultimately sensitizing CRC cells to ferroptosis. Additionally, CLK2 promoted CRC proliferation and tumorigenesis in patient-derived organoids, cell lines, and mouse models. Furthermore, combining the ferroptosis inducer Erastin with Oxaliplatin significantly enhanced anti-tumor efficacy in CLK2-deficient xenograft models. Together, this study establishes CLK2 as a critical inhibitor of ferroptosis via the KEAP1/NRF2/HMOX1 and p53/SLC7A11 axes, supporting its potential as a therapeutic target for CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4949
Front Immunol. 2025 ;16 1611375

FASN promotes the stemness of cancer stem cells and protects colorectal cancer cells from ferroptosis by inhibiting the activation of SREBP2.

Ming Wang, Fulin Ge, Cheng Wu, Binbin Su, Xiaoyu Dong, Shiping Xu, Hui Shi.

   Introduction: Fatty acid synthase (FASN) is a key regulator of lipid metabolism, but its role in colorectal cancer (CRC) stemness and ferroptosis remains unclear.
Methods: FASN expression in CRC was analyzed using TCGA data and validated in CRC cell lines (CACO-2, HCT116, SW480) and normal HIEC-6 cells via qRT-PCR and Western blot. HCT116 cells (highest FASN expression) were used for experiments. FASN silencing (shRNA) effects on CSCs were assessed via 3D spheroid formation and CD133+CD44+ flow cytometry. In vivo tumor growth was tested in BALB/c nude mice. Mechanistic assays included cholesterol detection, SREBP2 Western blot, fatostatin rescue experiments, ferroptosis markers (ferrous ions, ROS, MDA, 4-HNE, mitochondrial function), and FASN-SREBP2 co-immunoprecipitation.
Results: FASN was overexpressed in CRC tissues (TCGA) and cell lines, with highest levels in HCT116. It was upregulated in 3D spheroids and CD133+CD44+ CSCs. FASN silencing reduced spheroid formation, in vivo tumor growth, and CD133+CD44+ cells. Mechanistically, FASN knockdown decreased cholesterol, activated SREBP2, and induced ferroptosis (elevated ferrous ions, ROS, lipid peroxidation, mitochondrial dysfunction); these effects were reversed by fatostatin. Co-IP confirmed FASN-SREBP2 interaction.
Discussion: FASN promotes CRC progression by enhancing CSC stemness and suppressing ferroptosis through SREBP2 inhibition, highlighting its potential as a therapeutic target.

Keywords:  FASN; cancer stem cells; colorectal cancer; ferroptosis; lipid metabolism

DOI:  https://doi.org/10.3389/fimmu.2025.1611375
Cell Signal. 2025 Aug 26. pii: S0898-6568(25)00497-8. [Epub ahead of print]136 112082

C20orf27 regulates colorectal cancer growth and metastasis based on different lipid levels.

Peng Xu, Haidi Guan, Guangsheng Du, Zhongwei Xu, Dong Xiong, Weidong Xiao, Xiufei Liu, Lihua Sun.

  Colorectal cancer (CRC) is a high-incidence malignant tumor that lacks highly effective targeted treatments currently. Epidemiology studies have revealed a direct association between high-fat diet intake and CRC. C20orf27, a key factor controlling adipose thermogenesis and glucose homeostasis, is abnormally overexpressed in CRC. However, its roles in CRC remain unknown. Therefore, our study aimed to reveal the clinical significance and biological function of C20orf27 in human CRC. Here, C20orf27 expression showed a positive correlation with patient body mass index values. Furthemore, we have demonstrated that C20orf27 promotes tumor proliferation while suppressing metastasis in CRC cells. However, under high-lipid induction conditions, C20orf27 exhibits paradoxical effects-inhibiting proliferation but enhancing metastatic potential in CRC cells. Moreover, we revealed that C20orf27 mediated CRC cell proliferation and metastasis through different signaling pathways (XBP1 or MST1) in the presence or absence of hyperlipidemia. In conclusion, our study showed the unique tumorigenic properties of C20orf27 in regulating CRC development and delineated the underlying mechanism by which it is affected by the lipid environment.

Keywords:  C20orf27; Colorectal cancer; Growth; Lipid; Metastasis

DOI:  https://doi.org/10.1016/j.cellsig.2025.112082
Cell Rep. 2025 Sep 02. pii: S2211-1247(25)00985-4. [Epub ahead of print]44(9): 116214

Organoids as models of immune-organ interaction.

Marius Francisco Harter, Timothy Recaldin, Nikolche Gjorevski.

  Incorporating immune cells into organoids enables exploring previously inaccessible aspects of immune-epithelial interactions in vitro. In this review, we start by detailing how immune-organoid co-cultures can model mucosal immunity at each stage of a functional inflammatory response. We then describe how inflammatory organoid systems have informed our understanding of the features driving chronic stress and remodeling in autoimmune diseases and explore how patient-derived carcinoma organoids can be combined with tumor-relevant immune compartments for oncology research. We conclude by highlighting gaps that warrant focus. The ultimate aspiration is to develop systems where homeostatic dynamics are established, maintained, and perturbed in a fully mature differentiated state and where immune memory can be acquired to pathogenic challenges de novo. This would enable interrogation of immune processes with increased control and higher throughput for hypothesis testing, ultimately deepening our understanding of human immune biology in health and disease.

Keywords:  CP: Immunology; CP: Stem cell research

DOI:  https://doi.org/10.1016/j.celrep.2025.116214
Nat Cancer. 2025 Aug 29.

Epigenomics and CRISPRi reveal cis-regulatory elements in colorectal cancer.

DOI: https://doi.org/10.1038/s43018-025-01032-y
bioRxiv. 2025 Aug 26. pii: 2025.08.21.671161. [Epub ahead of print]

Loss of WNT2B Increases Progression from Dysplasia to Colorectal Cancer.

Luiz Fernando Silva Oliveira, Yu-Syuan Wu, Sathuwarman Raveenthiraraj, Jaedeok Kwon, Venkata Siva Dasuri, Comfort Adegboye, Juan Putra, Jorge O Munera, Diana L Carlone, David T Breault, Amy E O'Connell.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in the United States, and upregulation of the WNT pathway is a primary driver in most cases. However, the role of individual WNT proteins in the development of CRC remains poorly understood. Our previous studies demonstrated that WNT2B loss-of-function leads to severe intestinal enteropathy in humans and increases chemically-induced colitis in mice, suggesting a protective function in the colon. Therefore, we investigated how loss of WNT2B affects CRC development. We used azoxymethane (AOM)/dextran sodium sulfate (DSS) to model colitis-associated cancer (CAC) and AOM-induced mutagenesis to model sporadic CRC. We measured the number and size of tumors and performed histopathological and molecular analyses. We also analyzed the Cancer Genome Atlas to evaluate WNT2B expression in human colon cancer. In CAC and CRC mouse models, Wnt2b KO mice showed decreased survival and enhanced tumor burden. Moreover, Wnt2b KO mice had larger tumors and enhanced dysplasia, with a higher frequency of animals progressing from adenomas to adenocarcinomas compared to control littermates. Wnt2b KO animals frequently presented with intestinal bleeding and rectum prolapse, which resembles obstructive CRC. Furthermore, WNT2B expression was downregulated in human CRC samples compared to healthy controls, which predicted a significantly lower patient survival. These findings support the conclusion that WNT2B is required for maximal resistance against tumorigenesis and raise the possibility that selectively increasing WNT2B signaling may be a useful colon cancer prevention strategy.
Significance: WNT2B loss-of-function increases colon cancer tumorigenesis. Targeting WNT2B may represent a novel strategy for intestinal diseases with a high risk of neoplastic transformation, potentially decreasing the progression to cancer development.

DOI: https://doi.org/10.1101/2025.08.21.671161
Br J Cancer. 2025 Aug 28.

Primary tumor sidedness and negative hyperselection to modulate anti-EGFR-based maintenance strategies in patients with RAS wild-type metastatic colorectal cancer: individual patient data pooled analysis of two randomized clinical trials.

Alexej Ballhausen, Federica Morano, Arndt Stahler, Sara Lonardi, Andreas Jay Kind, Chiara Cremolini, Susanna Swoboda, Giovanni Randon, David Horst, Michele Prisciandaro, Annabel Helga Sophie Alig, Chiara Carlotta Pircher, Armin Jarosch, Paola Andena, Annika Kurreck, Anna Alessandra Chiaramonte, Sebastian Stintzing, Filippo Pietrantonio, Dominik Paul Modest, Alessandra Raimondi.

BACKGROUND: Patients with RAS wild-type (WT), left-sided metastatic colorectal cancer (mCRC), negatively hyperselected for anti-EGFR resistance alterations, benefit most from anti-EGFR-based first-line treatment. The predictive impact of these stratification parameters on maintenance strategy efficacy is unclear.
METHODS: This pooled analysis included individual patient data from the PanaMa (NCT01991873) and Valentino (NCT02476045) phase 2 trials. Patients with RAS WT mCRC received FOLFOX plus Panitumumab induction therapy followed by maintenance with 5-fluorouracil/leucovorin (5-FU/LV) plus Panitumumab vs. 5-FU/LV monotherapy (PanaMa) or Panitumumab monotherapy (Valentino). Outcomes included progression-free survival (PFS) and overall survival (OS). Subgroup analyses examined primary tumor sidedness (left vs. right) and hyperselection status (negative vs. altered).
RESULTS: Among 607 patients receiving induction, sidedness and hyperselection status were available for 589 and 511 patients, respectively. Left-sided and negative hyperselected tumors were observed in 80.2% and 63.9% of patients, respectively. Panitumumab-based maintenance improved PFS in left-sided, negative hyperselected patients compared to 5-FU/LV alone, with no OS differences. PFS and OS were comparable for Panitumumab alone vs. Panitumumab plus 5-FU/LV.
CONCLUSION: Tumor sidedness and hyperselection status significantly influence maintenance strategy efficacy in mCRC. For left-sided, negative hyperselected patients, Panitumumab monotherapy may optimize efficacy while minimizing toxicity. Further investigation into the relative contribution of individual hyperselection parameters in this setting is warranted.

DOI: https://doi.org/10.1038/s41416-025-03164-5
Res Sq. 2025 Aug 27. pii: rs.3.rs-7133814. [Epub ahead of print]

Rapid activation of ARF6 after RAF inhibition augments BRAFV600E and promotes therapy resistance.

Allie Grossmann, Junhua Wang, Yinshen Wee, Thomas Jacob, Aaron Rogers, Lise Sorensen, Deja Brooks, Prachi Gupta, Joshua Tay, Emily Wilson, Tong Liu, Eric Smith, Vashisht Yn, Michael Davies, Martin McMahon, Sheri Holmen, Robert Judson-Torres, Roger Wolff.

The intrinsic ability of cancer cells to evade death underpins tumorigenesis, progression, metastasis and the survival of drug-tolerant persister (DTP) cells. Herein, we discovered that when activated, the small GTPase ARF6 plays a central role in tumor survival by facilitating expression of the BRAF V600E oncoprotein. Tumor-specific Arf6 deletion caused a significant reduction in BRAF V600E protein and MAPK signaling and prevented rapid tumor progression. In the context of targeted therapy, BRAF inhibition induced swift activation of ARF6, driving a positive feedback loop that restored MAPK-driven anti-apoptotic signaling, facilitated DTP cell survival during the early phases of treatment and contributed to drug-tolerant growth. In patient-derived melanoma cells with innate or clinically acquired resistance to MAPK inhibitors, ARF6 inhibition enhanced sensitivity to combined BRAF + MEK inhibition. Collectively, these findings elucidate an ARF6-dependent mechanism of BRAF oncoprotein synthesis that may be exploited in BRAF V600E driven cancers as a therapeutic vulnerability.

DOI: https://doi.org/10.21203/rs.3.rs-7133814/v1
Cell Res. 2025 Aug 29.

Novel organoid culture condition: modeling fetal-like plasticity in colorectal cancer.

Chao Wu, Min Jung Kim, J Joshua Smith.

DOI: https://doi.org/10.1038/s41422-025-01170-z
Cancer Cell. 2025 Aug 21. pii: S1535-6108(25)00340-X. [Epub ahead of print]

Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer.

Van K Morris, Christine M Parseghian, Vahid Bahrambeigi, Nourhan Abdelfattah, Lianchun Xiao, Anjali Agrawal, Kangyu Lin, Kanwal P S Raghav, Robert A Wolff, Arvind Dasari, Ryan W Huey, Bryan K Kee, Michael J Overman, Jason A Willis, Phat H Le, Michelle Escano, Yunyu C Baig, Kelsey Pan, David Menter, Alda L Tam, Wai C Foo, Li Shen, Hey Min Lee, Thomas D Gallup, Cori Margain, Dave Gallup, Kimal I Rajapakshe, Paola A Guerrero, Jing Wang, Ryan B Corcoran, Anirban Maitra, Kyuson Yun, Scott Kopetz.

  The BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (EGFR) antibody cetuximab modestly improve survival for patients with microsatellite stable (MSS) BRAFV600E metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAFwild-type colorectal cancer (CRC). In this phase 1/2 study (NCT04017650) of 26 participants with MSS BRAFV600E mCRC who received encorafenib, cetuximab, and anti-PD-1 antibody nivolumab, we report an overall response rate of 50% (95% confidence interval [CI] 29-71) and median progression-free survival of 7.4 months (95% CI, 5.6-9.6). Transcriptomic profiling of pretreatment biopsies and extracellular vesicle RNA (evRNA) isolated from plasma show enrichment of non-canonical mitogen-activated protein kinase (MAPK) signaling and immune activation signatures for responders. Complement pathway activation enriches in non-responder biopsies. On serial evRNA profiling, decreased MAPK signature and increased interferon gamma response signature associate with sustained treatment benefit. MSS BRAFV600E mCRC with baseline MAPK activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation.

Keywords:  BRAF; MAPK; PD-1; biomarker; clinical trial; colorectal cancer; complement pathway; evRNA; immunotherapy; metastasis; targeted therapy

DOI:  https://doi.org/10.1016/j.ccell.2025.08.002
bioRxiv. 2025 Aug 25. pii: 2025.08.21.671520. [Epub ahead of print]

FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.

Masayoshi Higuchi, August F Williams, Anna E Stuhlfire, Ariel H Nguyen, David A G Gervasio, Claire E Turkal, Suejean Chon, Matthew J Hangauer.

Cancer persister cells populate minimal residual disease and contribute to acquired drug resistance. We previously discovered that persister cells are sensitized to ferroptosis. However, our understanding of this emergent persister cell vulnerability remains limited, impeding ferroptosis drug development efforts. Here, we sought to understand key factors which govern persister cell ferroptosis to inform combinatorial treatment strategies. We found that persister cells can downregulate oxidative phosphorylation, a key source of reactive oxygen species, to avoid death from GPX4 inhibition. However, this can be overcome by pretreatment with clinically available histone deacetylase inhibitors which induce reactive oxygen species in persister cells and synergize with GPX4 inhibition. Furthermore, we found that while levels of iron, glutathione, and antioxidant genes are not universally dysregulated in persister cells, persister cells consistently downregulate alternative ferroptosis suppressor FSP1 and rely upon residual FSP1 to survive GPX4 inhibition. These findings reveal new strategies to eliminate persister cells by combining GPX4 inhibitors with histone deacetylase or FSP1 inhibitors.

DOI: https://doi.org/10.1101/2025.08.21.671520
Cell Death Dis. 2025 Aug 28. 16(1): 653

ACTL6A depletion induces KLF4-mediated anti-tumorigenic effects in colorectal cancer.

Hye-Ju Yang, Eun-Ju Kim, Yeonsoo Kim, Youngwon Cho, Younghee Choi, Sang-Hyun Song, Tae-You Kim.

ACTL6A, a subunit of the SWI/SNF and INO80 chromatin remodeling complexes, is frequently overexpressed in various cancers, and its depletion attenuates cell proliferation in colorectal cancer (CRC). However, the epigenetic mechanisms underlying ACTL6A function remain poorly understood. Here, we aimed to elucidate how ACTL6A regulates chromatin accessibility and gene expression in CRC. Integrated multi-omics analyses revealed that ACTL6A deficiency alters chromatin accessibility and upregulates P53 pathway-related genes, accompanied by the recruitment of SWI/SNF and INO80 complexes. Mechanistically, ACTL6A depletion enhances KLF4 binding at newly accessible regions, where it cooperates with these chromatin remodeling complexes to activate P53 pathway-related genes and induce apoptosis. ACTL6A contributes to CRC cell proliferation by inhibiting the KLF4-mediated transcriptional activation of tumor-suppressive genes. Thus, our findings highlight that targeting ACTL6A may serve as a promising therapeutic strategy in CRC.

DOI: https://doi.org/10.1038/s41419-025-07946-w
Stem Cell Rev Rep. 2025 Aug 29.

Metabolic Plasticity and Cancer Stem Cell Metabolism: Exploring the Glycolysis-OXPHOS Switch as a Mechanism for Resistance and Tumorigenesis.

Li Qing Keoh, Ching-Feng Chiu, Thamil Selvee Ramasamy.

  Metabolic plasticity is a hallmark of cancer, enabling tumour cells to grow and adapt to microenvironmental stress, eventually contributing to tumour heterogeneity. Although glycolysis-oxidative phosphorylation (OXPHOS) switch plays a pivotal role, emerging evidence highlights OXPHOS as an essential mechanism for cancer survival, particularly during metastasis and therapeutic stress, underscoring the complexities underlying metabolic plasticity and tumour heterogeneity. The role of glycolysis-OXPHOS switch in cancer stem cells (CSCs), a highly aggressive and drug-resistant population frequently enriched in response to the stress of tumour growth and pressure from microenvironmental or therapeutic cues, remains an open question with therapeutic interventions yielding mixed outcomes. While some strategies suppress CSC activity, others inadvertently promote resistance and tumour aggressiveness, thus contributing to treatment failure and relapse. This review critically examines the role of glycolysis-OXPHOS switch as a gatekeeper of tumorigenesis which influences CSC plasticity and resistance. By dissecting these metabolic dynamics, it aims to inform novel therapeutic strategies, emphasising tailored approaches to target CSC plasticity and improve cancer treatment outcomes.

Keywords:  Cancer stem cell; Glycolysis; Metabolic plasticity; Oxidative phosphorylation; Resistance

DOI:  https://doi.org/10.1007/s12015-025-10956-y
Discov Oncol. 2025 Aug 28. 16(1): 1648

HADHB mediates 5-fluorouracil sensitivity in colorectal cancer.

Xue Zhang, Hui Jin, Dan Li, Jiayin Liu, Jing Han.

   PURPOSE: 5-Fluorouracil (5FU) is a primary chemotherapy for colorectal cancer (CRC), but resistance reduces its effectiveness. HADHB, important in mitochondrial fatty acid β-oxidation, is linked to tumor metabolism changes in various cancers. Its potential influence on 5FU sensitivity in CRC remains unclear. This study aims to elucidate the role of HADHB in modulating 5FU sensitivity in CRC.
METHODS: Collect CRC tissue samples treated with 5FU and perform immunohistochemical staining to evaluate the relationship between HADHB expression and 5FU efficacy. We assessed the impact of HADHB on 5FU IC50 in CRC cells via CCK-8, confirmed HADHB-DUOX2 interaction through co-IP, and used fluorescence staining and flow cytometry to measure ROS levels. Metabolomics and transcriptomics were employed to investigate DUOX2-related metabolic pathways.
RESULTS: HADHB was significantly upregulated in 5FU-resistant CRC tissues compared to sensitive ones. HADHB knockdown in CRC cell lines improved 5FU sensitivity, increased apoptosis, and caused cell cycle arrest. We identified DUOX2 as a novel HADHB-interacting protein, with their protein levels showing strong positive correlation. Silencing either HADHB or DUOX2 can result in a decrease in ROS production, while DUOX2 overexpression reversed the ROS reduction caused by HADHB knockdown, thereby establishing a functional connection between these two elements in the regulation of ROS. This mechanism may play a crucial role in modulating the sensitivity to 5FU mediated by HADHB.
CONCLUSION: HADHB overexpression is linked to 5FU resistance in CRC, indicating it as a potential therapeutic target, likely via the HADHB-DUOX2-ROS pathway.

Keywords:  5-Fluorouracil sensitivity; Colorectal cancer; HADHB; ROS

DOI:  https://doi.org/10.1007/s12672-025-03503-1
Gut Microbes. 2025 Dec;17(1): 2547029

Gut microbiota dysbiosis affects intestinal sensitivity through epithelium-to-neuron signaling: novel insights from a colon organoid-based model to improve visceral pain therapy.

Francesco Margiotta, Elena Lucarini, Alessandra Toti, Lorenzo Curti, Alessio Masi, Tommaso Mello, Gwenaelle Le Gall, Gianluca Mattei, Alberto Magi, David Vauzour, Guido Mannaioni, Lorenzo Di Cesare Mannelli, Carla Ghelardini.

  Chronic gastrointestinal pain is a hallmark of most intestinal pathologies, yet effective treatments remain elusive given the complexity of the underlying mechanisms. Aiming to investigate the intestinal epithelium contribution to visceral pain modulation in dysbiosis context, we first demonstrated that intracolonic instillation of microbe-free fecal supernatants from mice with post-inflammatory dysbiosis induced by dextran sodium sulfate (FSDSS) provokes visceral hypersensitivity in recipient mice. Epithelium involvement in the response to FSDSS was analyzed through a novel in vitro approach comprising murine epithelial colon organoids and primary dorsal root ganglia (DRG) neurons. FSDSS treatment induced growth and metabolic impairment in colon organoids, which revealed a dysbiosis-driven epithelial dysfunction. Notably, the combination of FSDSS and conditioned medium from FSDSS-treated colon organoids induced an increase in DRG neuron intrinsic excitability, along with greater immunoreactivity to c-Fos and calcitonin-gene related peptide, implicating an integrated role of both microbial and epithelial products in visceral sensitivity regulation. By investigating the underlying signaling, metabolomic analysis revealed reduced levels of short chain fatty acids in FSDSS, such as butyrate, acetate, valerate, and propionate. Moreover, transcriptomic analysis of FSDSS-treated colon organoids showed the dysregulated expression of several signaling factors by which intestinal epithelium may modulate sensory neuron excitability, including proteases, cytokines, neuromodulators, growth factors, and hormones. These findings provide novel insights into the role of gut epithelium in the modulation of sensory neuron excitability under dysbiosis conditions, emphasizing that targeting epithelial-neuronal signaling might represent a promising therapeutic strategy for visceral pain management.

Keywords:  DRG neurons; Visceral pain; dysbiosis; epithelial-neuronal signaling; intestinal epithelium; microbiota; organoids

DOI:  https://doi.org/10.1080/19490976.2025.2547029
bioRxiv. 2025 Aug 22. pii: 2025.08.18.670963. [Epub ahead of print]

Intestinal catabolism of dietary fructose promotes obesity and insulin resistance via ileal lacteal remodeling.

Miranda L Lopez, Taekyung Kang, Ana Espeleta, Varvara I Rubtsova, Jongwon Baek, Jakob Songcuan, Elena M Moyer, Joohwan Kim, Won-Suk Song, Sunhee Jung, Nicholas D'Sa, Alexis Anica, Elise Tran, Yujin Chun, Wonsuk Choi, Ki-Hong Jang, Miranda E Kelly, Ian J Tamburini, Yasmine H Alam, Johnny Le, Cuauhtemoc B Ramirez, Raghu P Kataru, Seon Pyo Hong, Dequina A Nicholas, Katherine S Xue, Gina Lee, Hosung Bae, Cholsoon Jang.

  High-fructose corn syrup (HFCS) consumption is a risk factor for obesity and metabolic syndrome, yet the underlying mechanisms are incompletely understood. Catabolism of dietary fructose primarily occurs in the small intestine and liver, with fructose breakdown in the liver being pathological, while small intestinal fructose clearance protects the liver. Here, we unexpectedly found that inhibition of fructose catabolism specifically in the small intestine mitigates fructose-induced obesity and insulin resistance. Mechanistically, blocking intestinal fructose catabolism reduces dietary fat absorption, which is associated with a decrease in the surface area of the ileal lacteals and alterations in gut microbiome. Fecal transplantation experiments revealed that such a microbiome stimulates the intestine-resident macrophages, promoting lacteal growth and boosting dietary fat absorption. Given the preclinical and clinical studies reporting the effect of fructose catabolism suppression on mitigating diet-induced obesity, our data suggest that such effects are partly mediated by intestinal lacteal remodeling.

Keywords:  Biological Sciences; Fructose; Ketohexokinase; Lacteals; Microbiota; Obesity; Physiology

DOI:  https://doi.org/10.1101/2025.08.18.670963
Cell Mol Gastroenterol Hepatol. 2025 Sep 02. pii: S2352-345X(25)00169-9. [Epub ahead of print] 101628

A single-cell atlas of transcriptome changes in the intestinal epithelium at the suckling-to-weaning transition in male rabbits.

Tania Malonga, Christelle Knudsen, Julie Alberge, Emeline Lhuillier, Patrick Aymard, Elisabeth Jones, Corinne Lencina, Manon Despeyroux, Elodie Riant, Cédric Cabau, Alyssa Ivy, Crystal L Loving, Nathalie Vialaneix, Martin Beaumont.

   BACKGROUND & AIMS: The suckling-to-weaning dietary transition is a key step in intestinal development. The aim of our study was to identify the transcriptome changes induced in each cell type of the intestinal epithelium at the onset of solid food ingestion.
METHODS: We compared the single-cell transcriptome of epithelial cells isolated from the caecum of age-matched littermate suckling male rabbits ingesting or not solid food.
RESULTS: Our dataset provides the first single-cell atlas of the rabbit intestinal epithelium and highlights the interest of the rabbit as a model for studying BEST4+ epithelial cells, which are absent in mice. Solid food ingestion induced extensive transcriptome changes in each epithelial cell type, with the most pronounced changes noted in absorptive and BEST4+ cells. Some of the effects of solid food introduction were common to most epithelial cell types, such as the upregulation of ALDH1A1. Solid food ingestion remodeled epithelial defenses systems, as observed by the increased expression of interferon-stimulated genes in mature absorptive and BEST4+ cells. Solid food upregulated the gene expression of the immunoglobulin transporter PIGR in cells located at the base of epithelial crypts and in goblet cells. In addition, solid food triggered epithelial differentiation, which was associated with modification of the expression of genes involved in handling of nutrients, as well as changes in hormone expression by enteroendocrine cells. These cell type-specific transcriptome modifications induced by solid food ingestion coincided with changes in microbiota composition and were replicated, in part, by butyrate in organoids.
CONCLUSIONS: Our work provides a single-cell atlas of the transcriptome changes induced in the intestinal epithelium at the suckling-to-weaning transition.

Keywords:  Weaning; early life; epithelium; gut; organoids; postnatal development; scRNA-seq

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101628
Nat Struct Mol Biol. 2025 Sep 02.

Addendum: Retinoic acid signaling is critical during the totipotency window in early mammalian development.

Ane Iturbide, Mayra L Ruiz Tejada Segura, Camille Noll, Kenji Schorpp, Ina Rothenaigner, Elias R Ruiz-Morales, Gabriele Lubatti, Ahmed Agami, Kamyar Hadian, Antonio Scialdone, Maria-Elena Torres-Padilla.

DOI: https://doi.org/10.1038/s41594-025-01661-y
Med Oncol. 2025 Aug 30. 42(10): 458

Machine learning integration of bulk and single-cell RNA-seq data reveals glycolytic heterogeneity in colorectal cancer.

Yuanyuan Du, Zefeng Miao, Peng Li, Dan Feng, Mulin Liu, Aifang Ji, Shijun Li.

  As one of the most prevalent malignancies worldwide, colorectal cancer (CRC) exhibits a strong metabolic dependency on glycolysis, which fuels tumor expansion and shapes an immunosuppressive microenvironment. Despite its clinical significance, the regulatory landscape and cellular diversity of glycolytic metabolism in CRC require systematic exploration. Multi-omics datasets (bulk/scRNA-seq and spatial transcriptomics) were analyzed to quantify glycolytic signatures. Core regulatory genes were selected via integrated pathway mapping and a machine learning framework incorporating five-feature selection algorithms. Cellular subpopulations were delineated by metabolic profiles, with niche interactions modeled through ligand-receptor network analysis. Findings were validated across multicenter cohorts. Our analyses identified a tumor subpopulation characterized by a High Glycolytic State (HGS), displaying elevated glycolytic signature alongside stem-like properties. Spatial profiling demonstrated relative enrichment of HGS cells in central tumor regions, potentially reflecting adaptation to nutrient-limited conditions. Among the molecular features associated with HGS maintenance, five candidate regulators (PFKP, ERO1A, FKBP4, HDLBP, HSPA5) showed correlation with unfavorable clinical outcomes. Our study characterizes the metabolic heterogeneity of CRC and suggests a potential role for HGS cells in shaping the tumor microenvironment. The molecular features identified here may offer insights into metabolic dependencies that could be explored for future therapeutic targeting.

Keywords:  Colorectal cancer; Glycolysis; Machine learning; Tumor microenvironment; scRNA-seq

DOI:  https://doi.org/10.1007/s12032-025-03007-6
Oncogenesis. 2025 Aug 30. 14(1): 34

Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse.

Lucile Bansard, Guillaume Laconde, Vanessa Delfosse, Tiphaine Huet, Margaux Ayeul, Emilie Rigal, Quentin Donati, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Luc Brunel, Baptiste Legrand, Alain Chavanieu, Anthony R Martin, Julie Pannequin, William Bourguet, Muriel Amblard, Jean Marc Pascussi.

Tumor recurrence is frequently attributed to drug-tolerant cancer cells. We previously demonstrated that downregulation of the Pregnane X Receptor (PXR, NR1I2) reduces chemoresistance and prevents colorectal cancer recurrence in xenograft mouse models. However, there is currently a lack of clinically-suitable PXR antagonists. In this study, we report the design and synthesis of a novel PXR agonist-based PROTAC (JMV7048) which promotes polyubiquitination and degradation of the human PXR protein via E3 CRBN ubiquitin ligase and 26S proteasome pathways. JMV7048 selectively degrades PXR in colon carcinoma, hepatoma, and pancreatic cancer cell lines, with no impact on primary human hepatocytes. Notably, JMV7048 reduces PXR protein expression in drug-tolerant colon cancer cells, sensitizing them to chemotherapy and significantly delaying cancer relapse in xenografted nude mice. These findings suggest that PXR-targeting PROTACs may serve as novel therapeutic agents to enhance the sensitivity of chemo-resistant cancer cells to chemotherapy.

DOI: https://doi.org/10.1038/s41389-025-00573-2
J Adv Res. 2025 Sep 01. pii: S2090-1232(25)00680-0. [Epub ahead of print]

FSP1 reduces exogenous coenzyme Q10 and inhibits ferroptosis to alleviate intestinal ischemia-reperfusion injury.

Tianli Shen, Xingjie Wang, Junxiang Zhang, Yuyao Lin, Lindi Cai, Kai Deng, Cancan Zhou, Guanglin Qiu, Jie Lian, Qinhong Xu, Zhengdong Jiang, Pengwei Zhao, Yunhua Wu, Shufeng Wang, Lin Fan, Xuqi Li.

   INTRODUCTION: Intestinal ischemia-reperfusion injury (IRI) is a critical condition often requiring emergency intervention. Ferroptosis, a form of regulated cell death driven by phospholipid peroxidation, plays a central role in its pathogenesis.
OBJECTIVE: This study aimed to explore whether CoQ10 could mitigate intestinal IRI by suppressing ferroptosis.
METHODS: We analyzed serum CoQ10 levels and inflammatory cytokines in patients with mesenteric artery embolism. In mice, intestinal IRI was induced by transient superior mesenteric artery ligation following two weeks of CoQ10 pretreatment. Histology, ELISA, immunoblotting, and RNA sequencing were used to assess therapeutic effects. To explore mechanisms, we used CRISPR/Cas9 to generate FSP1 and COQ2 knockouts in enterocytes, along with targeted metabolomics and co-autoxidation assays. In vivo loss of FSP1 function was induced by AAV9 to evaluate its role in CoQ10-mediated protection.
RESULTS: Utilizing both our own and publicly available intestinal IRI cohorts, we identified a correlation between elevated CoQ10 levels and reduced systemic inflammation, along with decreased oxidized lipid accumulation in ischemia-reperfusion-affected small intestines. Transcriptomic enrichment analyses and biochemical assays demonstrated that CoQ10 supplementation effectively mitigates IRI by modulating lipid metabolism and inhibiting lipid peroxidation and ferroptosis. To elucidate the mechanism of action of CoQ10 against lipid peroxidation and ferroptosis, we established an in vitro ferroptosis-associated intestinal IRI model using enterocytes, which revealed that the CoQ10-mediated suppression of ferroptosis is dependent on FSP1. Targeted metabolomics analyses and co-autoxidation assays indicated that FSP1 suppresses ferroptosis by reducing CoQ10, thereby preventing phospholipid peroxidation. Loss of function FSP1 generated by genetic and pharmacological mechanisms in enterocytes or mouse intestines led to a decrease in the levels of reduced CoQ10, negating the therapeutic effects of CoQ10 on intestinal IRI.
CONCLUSION: Our study reveals a crucial role of CoQ10 in ferroptosis and highlights the potential of CoQ10 as a promising target for intestinal IRI treatment.

Keywords:  FSP1; Intestinal ischemia-reperfusion injury; Phospholipid peroxidation; coenzyme Q10; ferroptosis

DOI:  https://doi.org/10.1016/j.jare.2025.08.065