bims-instec 2026-06-28 papers

bims-instec

Biomed News

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

Issue of 2026–06–28
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis.
Fasting primes small intestinal regeneration after damage via a microbiome-metabolite-chromatin axis.
Dynamics and master transcription factors dependence of intestinal super-enhancers during differentiation and oncogenesis.
CD109 Drives Stemness and Chemoresistance in Colorectal Cancer via LRRC8A/AKAP12/PKCα-Mediated STAT3 Activation and WNT Signaling.
Immune cell-intrinsic STING activation drives tumor ferroptosis via AA-mediated suppression of ACSL4 lactylation in colorectal cancer.
When metastatic colorectal cancer becomes refractory: how can we optimize treatment?
Glucose starvation induces fumarate hydratase succinylation and inhibits ferroptosis to maintain colon cancer cell proliferation.
Hypoxia-mediated chromatin accessibility reprogramming of CA9 induces treatment resistance in colorectal mucinous adenocarcinoma.
Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.
Sleep Deprivation Promotes Colorectal Cancer in ApcMin/+ Mice Associated with Modulation of Gut Microbiota and Related Metabolites.

Cell Stem Cell. 2026 Jun 22. pii: S1934-5909(26)00205-5. [Epub ahead of print]

Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis.

Saori Goto, Vikram Deshpande, Ömer H Yilmaz, Norihiro Goto.

  Colorectal cancer (CRC) liver metastases are the leading cause of CRC-related mortality, yet the genetic and epigenetic drivers underlying this process remain poorly understood. Here, we established a pro-metastatic CRC organoid library through serial orthotopic transplantation of liver metastasis-derived organoids. Integrative RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses identified a pro-metastatic signature characterized by multilineage plasticity, including fetal-like and basal-like/squamous transcriptional programs. Motif and transcription factor activity analyses identified GATA6 as a key regulator of these epigenetic alterations. GATA6 expression is downregulated in liver metastases, and its genetic ablation enhances liver metastasis with minimal effects on primary tumor growth. Mechanistically, GATA6 loss triggers pro-metastatic transcriptional programs, including fetal-like and basal-like/squamous states, accompanied by LGR5- cell generation. This reprogramming is mediated by the direct repression of HNF4A and increased H3K27ac and occurs independently of SOX17. Together, these findings identify GATA6 loss as a central regulator of multilineage plasticity that drives liver metastasis in CRC.

Keywords:  colorectal cancer; metastasis; organoid

DOI:  https://doi.org/10.1016/j.stem.2026.05.013
Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2529215123

Fasting primes small intestinal regeneration after damage via a microbiome-metabolite-chromatin axis.

Praveen Barrodia, Ajay Kumar Saw, Sabrina L Jeter-Jones, Chia-Chi Chang, Jiansu Shao, Emre Arslan, Anand K Singh, Suresh Satpati, Robert R Jenq, Kunal Rai, Helen Piwnica-Worms.

  Fasting enhances small intestinal regeneration after radiation, but the contribution of the gut microbiome to this process remains uncharacterized. We identify Akkermansia muciniphila (AKK) as a key mediator of this response. AKK was enriched in fasted mice and its antibiotic depletion abrogated radioprotection, whereas reintroduction restored both organismal survival and intestinal integrity. Fasting elevated propionic acid, consistent with AKK's metabolic output. AKK-conditioned medium and propionate induced histone H3 acetylation in intestinal stem cell cultures while in vivo fasting induced AKK-dependent H3K27ac and H3K9ac, remodeling promoter-enhancer landscapes in crypt epithelial cells. Epigenetic profiling revealed a rewired core regulatory program enriched for pioneer transcription factors (Foxa, Gata, Klf), architectural organizers (Ctcf, Boris), and lineage-defining and metabolic regulators (Cdx2, Hnf4). This program supports expansion of a population of primed persister cells characterized by open chromatin accessibility at key stem and regenerative-associated loci including Clu, Olfm4, Lgr5, Ascl2, Lrig1, Sox9, Rnf43, and Axin2. These findings define a fasting-induced microbiome-metabolite-chromatin axis that epigenetically primes highly plastic persister cells for rapid regeneration of the intestinal epithelium following radiation-induced injury.

Keywords:  fasting; microbiome; radiation; regeneration; stem cell

DOI:  https://doi.org/10.1073/pnas.2529215123
Nucleic Acids Res. 2026 Jun 22. pii: gkag634. [Epub ahead of print]54(12):

Dynamics and master transcription factors dependence of intestinal super-enhancers during differentiation and oncogenesis.

Wenxin Fang, Shuya Huang, Ruoxuan Xiao, Guangling Wei, Mingyang Zhang, Xia Qiu, Li Zou, Michael P Verzi, Yan Wang, Lei Chen.

The intestinal epithelium is a highly regenerative tissue organized along the crypt-villus axis, where spatially compartmentalized gene expression governs stem cell renewal, proliferation, and differentiation. Super-enhancers (SEs) are large clusters of regulatory elements densely bound by transcription factors (TFs) and cofactors that drive high-level expression of genes controlling cell identity and fate, yet their roles in intestinal epithelial identity and differentiation remain unclear. Here, we generate a spatiotemporal map of SEs in the small intestine, identifying compartment-specific SEs that define crypt and villus programs. Using mouse genetic models, we identify CDX2, HNF4, and SMAD4 as core TFs orchestrating SE-driven transcriptional networks essential for epithelial differentiation. CDX2 is required for SE integrity, and its loss causes widespread SE collapse and silencing of intestinal identity genes. We further demonstrate SE remodeling during colorectal cancer, in which HNF4 and SMAD4 function as SE-associated tumor suppressors that restrain oncogenic enhancer programs. Together, our findings establish SEs as central regulators of intestinal architecture, epithelial fidelity, and tumor progression.

DOI: https://doi.org/10.1093/nar/gkag634
Int J Biol Sci. 2026 ;22(11): 6064-6083

CD109 Drives Stemness and Chemoresistance in Colorectal Cancer via LRRC8A/AKAP12/PKCα-Mediated STAT3 Activation and WNT Signaling.

Rubén A Bartolomé, Tania Calvo-López, Pablo Otero-Núñez, María Estaras, Asunción Fernández-Barral, Antonio Barbáchano, Issam Boukich, María Cuerda-López, Mª Jesús Fernández-Aceñero, Gorane Rodríguez-Urquirizar, Ana Mariscal-Casero, Miguel Padilla-Blanco, María Montoya, Ana O'Loghlen, José M Fernández-Fernández, Jose Manuel Gonzalez-Sancho, J Ignacio Casal.

  Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide, with a poor survival rate at the metastatic stage. Here, we identify CD109-a negative regulator of TGFβ signaling-as a key driver of stemness and drug resistance through modulation of Wnt signaling in advanced CRC. CD109 expression strongly correlates with TGFβ levels in patient tumors and is enriched in the aggressive CRIS-B subtype, where it associates with poor clinical outcome. CD109 silencing reduced STAT3 phosphorylation and cell proliferation, without affecting migration or invasion. Moreover, global expression analysis revealed downregulation of various hallmarks of cancer stemness (i.e. LGR5 expression), together with increased TGFβ signaling and cellular senescence. Mechanistically, CD109 interacts with LRRC8A, a subunit of the volume-regulated anion channel (VRAC), which associates with AKAP12 to activate PKCα and promote STAT3 phosphorylation. This CD109/LRRC8A/AKAP12/PKCα axis sustains Wnt signaling, stemness, and drug resistance. Consistently, co-expression of CD109/LRRC8A/AKAP12 correlates with poor prognosis in CRC patients. Genetic or pharmacological disruption of this CD109/LRRC8A/AKAP12/PKCα axis impaired STAT3 signaling, reduced LGR5 expression and Wnt signaling, and sensitized cells to chemotherapy. In vivo, CD109 or LRRC8A knockdown significantly impaired liver homing and metastatic colonization in mouse models, showing stronger effects in Swiss nude mice than in highly immunodeficient NSG mice. Collectively, these findings support CD109 as a central regulator for STAT3-driven stemness and chemoresistance in advanced CRC, via the LRRC8A/AKAP12/PKCα axis, and highlight its potential value as a therapeutic target in metastatic disease.

Keywords:  AKAP12; CD109; LRRC8A; STAT3; TGFβ signaling; Wnt signaling; chemoresistance; colorectal cancer; metastasis

DOI:  https://doi.org/10.7150/ijbs.127856
Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2524594123

Immune cell-intrinsic STING activation drives tumor ferroptosis via AA-mediated suppression of ACSL4 lactylation in colorectal cancer.

Lina Ding, Wenqi Du, Jing Zhu, Yuxiang Zhang, Xingyue Wang, Linfeng Li, Buhui Liu, Xiaohong Wang, Qingling Wang, Dongsheng Pei.

  Ferroptosis has emerged as a key effector mechanism in antitumor immunity, yet the transcellular metabolic cross talk that modulates ferroptotic sensitivity in colorectal cancer (CRC) remains incompletely understood. Here, we describe an integrative regulatory axis linking immune cell-intrinsic Stimulator of Interferon Genes (STING) signaling to tumor ferroptosis through coordinated lipid metabolism and posttranslational modifications (PTMs). Mechanistically, STING activation in immune cells triggers TANK-binding kinase 1 (TBK1)-dependent phosphorylation of cytosolic phospholipase A2 (cPLA2) at Ser505, thereby releasing arachidonic acid (AA) into the tumor microenvironment (TME). This immune-derived AA is taken up by adjacent CRC cells, where it promotes ACSL4-dependent ferroptosis by inhibiting EP300-mediated lactylation of ACSL4 at lysine 426 (K426). In vivo, pharmacological activation of STING enhances AA release and facilitates ferroptosis-mediated tumor suppression. Notably, STING agonist synergizes with PD-1 checkpoint blockade to inhibit tumor progression, which is reversed by the ferroptosis inhibitor. Collectively, our findings establish an integrative and transcellular immunometabolic framework linking innate immune sensing to tumor ferroptosis, providing a strong rationale for combinatorial therapeutic strategies in CRC.

Keywords:  STING signaling pathway; arachidonic acid; ferroptosis; lactylation

DOI:  https://doi.org/10.1073/pnas.2524594123
Expert Opin Pharmacother. 2026 Jun 25. 1-3

When metastatic colorectal cancer becomes refractory: how can we optimize treatment?

Jane E Rogers.



Keywords:  Colorectal cancer; HER2; KRAS; epidermal growth factor receptor; metastatic; refractory

DOI:  https://doi.org/10.1080/14656566.2026.2689551
Cell Death Dis. 2026 Jun 22.

Glucose starvation induces fumarate hydratase succinylation and inhibits ferroptosis to maintain colon cancer cell proliferation.

L T Sun, X H Qin, Y D Zheng, Z Y Zhang, Q Wang.

Cancer cells frequently reside in a glucose-deprived microenvironment due to rapid tumor proliferation and insufficient angiogenesis. However, the mechanisms by which colorectal cancer cells (CRC) adapt to glucose starvation to sustain proliferation remain unclear. Succinylation, a novel post-translational modification, has been implicated in regulating tumor cell proliferation and survival under nutrient stress. Our study reveals that fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, is downregulated in CRC and acts as a tumor suppressor. Under glucose starvation mimicked in vitro, FH protein expression is reduced, leading to abnormal accumulation of its upstream metabolites fumarate and succinate, which correlates with advanced clinical stage and poor prognosis in CRC patients. Mechanistically, accumulated fumarate specifically binds to and stabilizes the NRF2 protein, upregulating the expression of GPX4 and FTH1 to inhibit ferroptosis, thereby sustaining CRC cell proliferation. Meanwhile, glucose starvation induces CPT1A-mediated succinylation of FH at residues K66/K80, reducing FH protein stability and promoting its degradation via the autophagy-lysosome pathway. Our findings reveal the critical role of FH and its succinylation in CRC cell adaptation to glucose starvation, inhibiting ferroptosis, and maintaining cancer cell proliferation, providing novel potential targets and a theoretical basis for the clinical treatment of CRC.

DOI: https://doi.org/10.1038/s41419-026-08975-9
J Gastroenterol. 2026 Jun 24.

Hypoxia-mediated chromatin accessibility reprogramming of CA9 induces treatment resistance in colorectal mucinous adenocarcinoma.

An Huang, Haopeng Hong, Zhuang Sun, Zhaoya Gao, Yong Yang, Jiajia Chen, Yonghui Sun, Zhengrong Li, Ming Li, Jin Gu.

   BACKGROUND: Mucinous adenocarcinoma (MAC) represents a subtype of colorectal cancer (CRC) characterized by insensitivity to chemoradiotherapy, necessitating urgent development of novel therapeutic strategies specifically targeting tumor biology of MAC.
METHODS: Integrated analysis of ATAC-seq and RNA-seq data was performed to identify pivotal targets mediating treatment resistance in MAC. Subsequently, clinical specimens were collected for immunohistochemistry, RT-qPCR, and Kaplan-Meier survival analysis. Functional validation of the target was conducted through in vitro experiments encompassing colony formation, drug sensitivity assessments, synergy testing, and immunofluorescence. The translational potential of the target was evaluated in vivo.
RESULTS: Integrated ATAC-seq and RNA-seq analyses identified hypoxia and dysregulated ferroptosis as critical features of MAC, screening carbonic anhydrase 9 (CA9) as a pivotal gene implicated in MAC treatment resistance. CA9-specific inhibitor synergized with 5-fluorouracil to exert enhanced antitumor effects. Additionally, CA9 knockdown or inhibition arrested tumor cell proliferation and migration, promoted intracellular reactive oxygen species generation, induced mitochondrial shrinkage, increased mitochondrial iron content, reduced glutathione levels, and triggered lipid peroxidation. Inhibitors of either ferroptosis or apoptosis antagonized CA9 inhibitor-mediated cell death. In vivo experiments demonstrated that CA9 knockdown or inhibition significantly delayed tumor growth. Co-immunoprecipitation revealed that CA9 interacts directly or indirectly with multiple ferroptosis-associated proteins.
CONCLUSION: This study identifies the hypoxic tumor microenvironments and dysregulated ferroptosis as pivotal molecular characteristics of MAC, and proposes a novel mechanism underlying treatment resistance in MAC: Hypoxia remodels chromatin accessibility through epigenetic modifications, to dysregulate CA9 expression, which may subsequently modulate cellular susceptibility to ferroptosis, culminating in treatment resistance, and targeting CA9 may improve the therapeutic efficacy of MAC, although further studies are needed to establish direct causality.

Keywords:  Chromatin accessibility; Colorectal cancer; Hypoxia; Mucinous adenocarcinoma; Treatment resistance

DOI:  https://doi.org/10.1007/s00535-026-02461-x
Nature. 2026 Jul;655(8121): 45-46

Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.

Amaia Zabala-Letona, Arkaitz Carracedo.



Keywords:  Biochemistry; Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-026-01802-3
Int J Biol Sci. 2026 ;22(11): 5895-5910

Sleep Deprivation Promotes Colorectal Cancer in ApcMin/+ Mice Associated with Modulation of Gut Microbiota and Related Metabolites.

Jia Chen, Rishun Su, Yong Kuang, Xiumin Liu, Yulong He, Jiong Chen, Changhua Zhang.

  Sleep deprivation (SD) has emerged as an important environmental factor associated with colorectal cancer (CRC); however, the underlying mechanisms, particularly those involving the gut microbiota-metabolite axis, remain poorly understood. In this study, ApcMin/+ mice, a well-established CRC model, were subjected to SD using a modified multiple-platform method. Fecal samples were analyzed using 16S rRNA gene sequencing and untargeted metabolomics, and tumor burden, intestinal inflammation, and gut barrier integrity were assessed by hematoxylin and eosin staining, immunofluorescence, and Alcian blue-periodic acid-Schiff staining. Our results showed that SD significantly aggravated CRC progression, as evidenced by an increase in tumor number and severity, impaired intestinal barrier integrity, and enhanced intestinal inflammation. In parallel, SD markedly altered the gut microbiota composition, characterized by a pronounced reduction in beneficial bacteria such as Lactobacillus. Metabolomic profiling revealed significant metabolic alterations, with taurocholic acid (TCA) identified as a prominently elevated metabolite. Transcriptomic and functional analyses suggested that TCA may be involved in CRC progression through the activation of the MAPK/ERK signaling pathway. Collectively, these findings support a model in which SD contributes to CRC progression in association with alterations in the gut microbiota and related metabolites.

Keywords:  colorectal cancer; gut microbiota; sleep deprivation; taurocholic acid

DOI:  https://doi.org/10.7150/ijbs.134241