bims-instec 2026-06-07 papers

bims-instec

Biomed News

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

Issue of 2026–06–07
eighteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Under pressure: peroxisomes in cancer therapy resistance.
EGFR deletion in myeloid cells reprograms the immunosuppressive landscape of colorectal cancer.
Plasticity in Cancer Cells: The Master Engine of Therapeutic Resistance and Tumor Evolution.
Modulation of intestinal bile acids influences colonic mucosal responses.
Genetic variants of the transporter SLC22A4 affect the abundance and survival of Fusobacterium nucleatum in colorectal cancer.
A progenitor cell population contributes to prenatal injury repair and neonatal antimicrobial defense in the small intestine.
The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.
HIF-1α integrates lipogenic FASN and glycolytic GLUT3 to overcome intratumor oxidative and hypoxic stress for colorectal cancer metastasis.
Vesicular QSOX1-MMP2 from inflammatory cancer-associated fibroblasts degrades the extracellular matrix to drive colorectal cancer pulmonary dissemination.
Spermine is an endogenous iron chelator that inhibits ferroptosis.
A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter SLC43A1 (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells.
Salmonella lipopolysaccharide stimulates uptake of long-chain fatty acids in the small intestine.
Mevalonate pathway rewiring driven by enhancer remodelling confers resistance to KRAS inhibitors in colorectal cancer.
Editorial: Unraveling GI cancer heterogeneity through single-cell multi-omics approaches.
Autogenic-regenerated intestinal transplantation improves outcomes in short bowel syndrome.
Single-cell transcriptome analysis reveals SOX9 mutation-driven tumor stemness and microenvironment remodeling through the COL1A1-CD44 axis in colorectal cancer.
Epigenetic heterogeneity and plasticity in therapy-induced tumor states through single-cell multi-omics.
l-Malic Acid Enhances Intestinal Stem Cell Expansion and Barrier Function via the Sirt2/β-Catenin Signaling Pathway.

Trends Mol Med. 2026 Jun 03. pii: S1471-4914(26)00110-3. [Epub ahead of print]

Under pressure: peroxisomes in cancer therapy resistance.

Nicla Lorito, Francesca Bonechi, Elisabetta Romano, Alfredo Smiriglia, Andrea Morandi.

  Therapy resistance is a major obstacle to durable clinical responses. While genetic alterations and signalling rewiring are primary drivers of resistance, metabolic adaptation, which is closely intertwined with these processes, enables tumour persistence under therapeutic pressure and directly contributes to resistance. Peroxisomes are metabolic organelles with a role in controlling lipid metabolism, together with redox signalling and homeostasis-processes that intersect with pathways governing cancer behaviour and therapy response. Indeed, peroxisomal functions are remodelled to support metabolic plasticity and redox buffering under therapeutic stress. In this review, we synthesise emerging evidence linking peroxisome biology to resistance to chemotherapy, targeted therapies, radiotherapy, and immunotherapy and discuss how peroxisomal pathways may be exploited therapeutically or as biomarkers to overcome cancer therapy resistance.

Keywords:  PPAR; ether phospholipids; fatty acid oxidation; pexophagy; redox homeostasis; therapy resistance

DOI:  https://doi.org/10.1016/j.molmed.2026.05.001
Cell Death Differ. 2026 Jun 02.

EGFR deletion in myeloid cells reprograms the immunosuppressive landscape of colorectal cancer.

Ourania Fari, Angelika Neuhofer, Martin Holcmann, Tatiana Chontorotzea, Iros Barozzi, Thomas Mohr, Bernadette Blauensteiner, Dana Krauß, Yu-Tian Xiao, Michaela Lang, Dario L Frey, Barbara Helm, Ursula Klingmüller, Matthias Farlik, Maria Sibilia.

Despite advances in the treatment of metastatic colorectal cancer (mCRC), it remains the second leading cause of cancer-related mortality, with limited effective therapeutic options. While EGFR inhibition is a standard first-line therapy for mCRC patients lacking KRAS mutations, resistance frequently develops, limiting its clinical benefit. Murine CRC models have shown that EGFR deletion in myeloid cells reduces tumor burden, and the presence of EGFR-positive myeloid cells is associated with poor prognosis in mCRC patients. However, the role of these cells in the therapeutic response to anti-EGFR therapies remains poorly understood. In this study, we integrated mouse models, single-cell RNA sequencing (scRNAseq), proteomics, and patient-derived mCRC datasets to investigate how EGFR signaling in myeloid cells shapes the tumor microenvironment (TME). In a preclinical therapeutic trial, we demonstrate that EGFR deletion in myeloid cells of tumor-bearing CRC mice reduced tumor growth, whereas EGFR loss in intestinal epithelial tumor cells alone had no therapeutic impact. EGFR deletion also decreased the abundance of F4/80hi macrophages, particularly the Spp1+ and C1qc+ subsets, and reduced inflammatory pathways like TGFβ, IFNγ, and JAK/STAT signaling in myeloid cells. These changes altered myeloid-T cell interactions, resulting in a less immunosuppressive TME characterized by reduced immune checkpoint expression. Furthermore, we identified thrombospondin-1 (THBS1) as a myeloid-derived ligand interacting with T cells, and confirmed its regulation by EGFR signaling through proteomic analysis. Analysis of human CRC datasets revealed that high EGFR and THBS1 expression correlates with poor patient outcomes. Collectively, these findings establish EGFR signaling in myeloid cells as a critical regulator of the immunosuppressive TME and suggest that targeting EGFR within specific myeloid subsets could represent a promising therapeutic strategy in mCRC.

DOI: https://doi.org/10.1038/s41418-026-01774-x
Curr Mol Med. 2026 May 25.

Plasticity in Cancer Cells: The Master Engine of Therapeutic Resistance and Tumor Evolution.

Afza Ahmad.

  Cancer cell plasticity refers to the ability of cancer cells to change their phenotype and is one of the primary requirements for metastasis. It is considered one of the main contributors to intratumoral heterogeneity, a key factor in the development of cancer, and is known to alter responses and resistance to different forms of therapy. However, tumour cells are impaired in various cellular signalling pathways, such as mitogen-activated protein kinases, phosphoinositide-3-kinases, Wnt, Hedgehog, and Notch, as well as in epithelial-mesenchymal transition (EMT) and phenotypic plasticity. Cancer stem cells (CSCs) are considered an integral part of tumour plasticity, as they have the capacity to proliferate, differentiate, and initiate the growth of tumours. Recent studies suggest that targeting signals from the tumor microenvironment, plasticity-related pathways, and epigenetic regulators may offer promising therapeutic options to improve long-term response and reduce phenotypic dysregulation. This approach, which emphasizes plasticity as a primary biological driving force rather than a secondary one, allows cancer cells to change from an epithelial, mesenchymal, stem cell, or dormant state to a drug-resistant state in response to environmental stimuli. Taken together, these results suggest that cellular plasticity is important in tumour development and treatment failure. Therefore, targeting pathways associated with plasticity, modifying the tumour microenvironment, and using adaptive therapies may improve long-term tumour control.

Keywords:  Plasticity; cancer stem cells; signalling pathways; stemness; tumor evolution

DOI:  https://doi.org/10.2174/0115665240472692260521045539
Sci Rep. 2026 Jun 03. pii: 17126. [Epub ahead of print]16(1):

Modulation of intestinal bile acids influences colonic mucosal responses.

Esther Wortmann, Tanja Groll, Anne Strigli, Kenneth Peuker, Colin Volet, Leona Arps, Rizlan Bernier-Latmani, Sebastian Zeissig, Katja Steiger, Moritz Middelhoff, Thomas Clavel.

   BACKGROUND: Elevated levels of secondary bile acids produced by the gut microbiome, in particular deoxycholic acid (DCA), influence epithelial cell proliferation and accelerate the development of colorectal cancer (CRC) under adverse dietary conditions, such as long-term, high fat intake. However, their effects on the intestinal epithelium have not been studied in detail.
AIM: To determine gut epithelial responses to bile acid modulation in vivo and in situ.
METHODS: We performed targeted colonization of gnotobiotic mice followed by single-cell RNA sequencing (scRNA-Seq) of colonic epithelial cells combined with immunostaining of human biopsies from: (i) an observational patient cohort with hyperproliferative polyps or cancer; (ii) an interventional study with bile acid-scavenging drugs.
RESULTS: Colonization of mice with a defined bacterial community including the 7α-dehydroxylating species Extibacter muris resulted in DCA production. ScRNA-Seq of colonic epithelial cells revealed increased cell density of bile acid-sensitive enterocytes but fewer stem cells, goblet cells, and transit amplifying cells in mice exposed to DCA. This was associated with increased expression of pyruvate dehydrogenase kinase (Pdk4) and decreased expression of mucin (Muc2). PDK expression was also increased in human hyperplastic polyps and adenomas, whilst MUC2 expression was reduced in adenomas and carcinomas compared to normal mucosa. In addition, treatment of ileostomy patients with chologenic diarrhea using bile acid sequestrants was associated with enhanced epithelial proliferation in colorectal biopsies.
CONCLUSION: This study provides insight into intestinal epithelial cell responses to bile acids and their potential clinical relevance.

Keywords:  Colorectal cancer; Gut epithelial proliferation; Gut microbiome; Secondary bile acids

DOI:  https://doi.org/10.1038/s41598-026-55206-4
Gut Microbes. 2026 Dec 31. 18(1): 2681818

Genetic variants of the transporter SLC22A4 affect the abundance and survival of Fusobacterium nucleatum in colorectal cancer.

Samah Chouaibi, Veronica Fertitta, Silvia Porreca, Leila Njim, Antonella Carcagnì, Gabriele Toietta, Gianluca Canettieri, Khadija Zouari, Maha Mastouri, Yosr Kadri, Giovambattista Pani.

  The intestinal microbiota influences colorectal cancer (CRC) development, but its interactions with the host's genetic profile during tumorigenesis are poorly understood. We quantified the CRC-associated pathobiont Fusobacterium nucleatum (F. nucleatum) and the commensal Escherichia coli (E. coli) in 99 cases of archival colorectal cancer and adjacent normal mucosa. Tissues were genotyped for the 503F variant of the Organic Cation Transporter OCTN1/SLC22A4. Colorectal cancer stem cells engineered to express the variant were infected with F. nucleatum in vitro. F. nucleatum was similarly present in colorectal cancer tissues and the adjacent normal mucosa, but the F. nucleatum/E. coli ratio was significantly higher in tumors (303.82 vs 30.86, p-value = 0.0396), in a fashion that steadily increased with the number of mutant SLC22A4 alleles (23.48, 159.56, and 211.03 for 0, 1, or 2 T alleles; p = 0.0215). Colon cancer spheroids overexpressing the 503F variant, but not the wild-type allele, displayed attenuated inflammatory response to F. nucleatum and impaired bacterial clearance, mechanistically linking SLC22A4 function and intratumoral F. nucleatum abundance. Thus, genetic variants of the intestinal carrier SLC22A4 shape the intratumor microbiota in favor of a pro-carcinogenic pathobiont by dampening innate immunity and increasing the tolerance of cancerous cells to bacterial invasion.

Keywords:  Colorectal cancer; Fusobacterium nucleatum; OCTN1; cancer stem cells; genetic variants; innate immunity; microbiota

DOI:  https://doi.org/10.1080/19490976.2026.2681818
Cell Rep. 2026 Jun 04. pii: S2211-1247(26)00581-4. [Epub ahead of print]45(6): 117503

A progenitor cell population contributes to prenatal injury repair and neonatal antimicrobial defense in the small intestine.

Yonghui Shen, Chunlin Li, Hanqiong Zhang, Huidong Liu, Lianzheng Zhao, Ye-Guang Chen.

  The specialized types and functions of epithelial cells in the adult small intestine have been well elucidated, but remain poorly understood in the embryonic small intestine. Through integrating single-cell RNA sequencing with functional studies using mouse and organoid models, we identify small intestinal sentinel progenitor cells (SISPCs), marked by Lysozyme1 (Lyz1), in the embryonic and neonatal mouse small intestine. Distinct from Lyz1+ Paneth cells, SISPCs exhibit dynamic spatiotemporal patterning and stemness features during intestinal development. Notably, embryonic SISPCs display strong stemness potential in the proximal small intestine, whereas embryonic Lgr5+ cells exhibit greater stem potency in the distal region. In addition, SISPCs play a crucial role in the prenatal intestinal injury repair via the DUSP-p38 signaling axis and contribute to the neonatal antimicrobial defense. Our findings reveal SISPCs play a pivotal role in gut homeostasis and defense during development, and suggest them as potential therapeutic targets for developmental gut disorders.

Keywords:  CP: developmental biology; CP: immunology; SISPCs; antimicrobial defense; embryonic small intestine; injury repair; stemness

DOI:  https://doi.org/10.1016/j.celrep.2026.117503
Nat Commun. 2026 Jun 03.

The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.

Hussein Issaoui, Lina Zawil, Lola Bellone, Diogo Goncalves, Rachel Paul, Léa Di Mascio, Sonia Núñez-Vázquez, Sandrine Marchetti, Johanna Chiche, Nicolas Nottet, Simon Le Goupil, Hadrien Laprade, Lucile Bansard, Yourae Hong, Rebecca Wall, Sabine Tejpar, Caroline Truntzer, François Ghiringhelli, Suresh Poudel, Helen M Beere, Douglas R Green, Julie Pannequin, Eric Chevet, Jean-Ehrland Ricci.

Most colorectal cancer (CRC) patients exhibit resistance to immune checkpoint blockade (ICB), limiting treatment efficacy. Activating the unfolded protein response sensor IRE1α in cancer cells can induce anticancer immune responses, yet its regulation remains unclear. Here we identify Dolichyl-Phosphate Mannosyltransferase 1 (DPM1) as a regulator of IRE1 expression and activity using BioID screen. Analysis of CRC patient RNA-sequencing data reveals that low DPM1 expression correlates with an IRE1-dependent transcriptional signature, increased immune infiltration, and improved ICB responses. Mechanistically, DPM1 ablation reduces protein glycosylation, causing chronic IRE1 activation in cancer cells and enhanced cytotoxic T cell-mediated immunosurveillance. Inhibition or knock-out of IRE1 reverses this effect. These findings establish DPM1 as a modulator of IRE1 activity that influences tumor immunogenicity, suggesting its potential as a therapeutic target to improve cancer immunotherapy outcomes.

DOI: https://doi.org/10.1038/s41467-026-73942-z
Oncogene. 2026 Jun 03.

HIF-1α integrates lipogenic FASN and glycolytic GLUT3 to overcome intratumor oxidative and hypoxic stress for colorectal cancer metastasis.

Yunyi Wang, Yuanyi Wei, Christopher Bailey, Gong Peng, Peng Zhang, Kunrong Cheng, Jean-Pierre Raufman, Yin Wang, Yan Liu.

Colorectal carcinoma (CRC) remains a leading cause of cancer mortality, largely due to metastasis. Solid tumors, including CRC, must adapt to intratumoral hypoxia and oxidative stress, but the tumor-cell programs that couple these pressures to metastatic competence remain unclear. Across human CRC cohorts and cell lines, HIF-1α was coordinately upregulated and co-expressed with the metabolic effectors GLUT3 and fatty-acid synthase (FASN), most prominently in metastatic lesions. Using HIF-1α (HRE), SREBP1 (SRE), and NRF2 (ARE) transcriptional reporters, we identified HRE-high and SRE-high CRC subpopulations with enhanced clonogenicity and invasion that drove accelerated tumor growth and increased lung metastatic burden across multiple CRC models. Mechanistically, IGF1 and insulin signaling through IGF1R and AKT-mTOR increased HIF-1α and induced FASN and GLUT3, enabling lipogenic, glycolytic, and antioxidant programs to withstand hypoxic and oxidative stress. HIF-1α engaged an HRE-containing proximal region of the human FASN promoter independently of SREBP1. Stress assays revealed functional specialization: FASN promoted NRF2-associated antioxidant capacity and resistance to oxidative injury, whereas GLUT3 preferentially supported hypoxia tolerance. In vivo, lipid nanoparticle-encapsulated echinomycin rapidly suppressed HRE, SRE, and ARE activity, reduced peri-hypoxic induction of FASN and GLUT3, inhibited tumor growth, and eliminated lung metastasis. These findings define a growth factor-responsive, HIF-1α-centered stress-adaptive state and highlight HIF-1α transcriptional activity as a therapeutic target in metastatic CRC.

DOI: https://doi.org/10.1038/s41388-026-03738-4
Cancer Lett. 2026 May 30. pii: S0304-3835(26)00408-8. [Epub ahead of print]656 218645

Vesicular QSOX1-MMP2 from inflammatory cancer-associated fibroblasts degrades the extracellular matrix to drive colorectal cancer pulmonary dissemination.

Tingwei Ye, Mengxi Chen, Yu Hu, Ziyan Yang, Jiayu Xu, Yongjie Zhang, Shenyue Zhou, Yuanyuan Yu, Yinshuang Chen, Zhoudong Zhang, MengMeng Wang, Jianqing Ruan, Weitao Zhang, Haiyang Zhang, Weichang Chen, Weipeng Wang.

  Pulmonary metastases represent a leading cause of mortality in colorectal cancer (CRC); however, the stromal mechanisms underlying metastatic colonization remain incompletely understood. Here, we show that extracellular vesicles (EVs) derived from inflammatory cancer-associated fibroblasts (iCAFs) are key promoters of CRC pulmonary metastasis (CRPM). Using single-cell RNA sequencing in a CRPM mouse model, we found that iCAFs constitute the predominant fibroblast population within the metastatic niche. Their differentiation was linked to NF-κB activation and SOCS3-mediated suppression of the TGF-β-Smad2/3 signaling pathway. Proteomic analysis further revealed selective enrichment of QSOX1 in iCAF-derived EVs. Functionally, QSOX1 binds to the N-terminal signal peptide (residues 1-29) of MMP2, suggesting that it may facilitate MMP2 secretion. Consistently, QSOX1 increased MMP2 abundance in EVs and enhanced EV-associated MMP2 activity, thereby facilitating degradation of the extracellular matrix (ECM) and enhancing the invasive capacity of CRC cells. Genetic knockdown of QSOX1 using siQsox1@LuT-LNPs, or its pharmacological inhibition with Ebselen, significantly reduced the lung metastatic burden and prolonged survival in vivo. Notably, Ebselen enhanced the anti-metastatic efficacy of anti-PD-L1 therapy to further suppress CRPM without augmenting toxicity. Our results establish EV-associated QSOX1-MMP2 as a pivotal regulator of metastatic niche remodeling and propose QSOX1 targeting, either alone or in combination with immune checkpoint blockade, as a promising therapeutic approach for CRPM.

Keywords:  Cancer-associated fibroblasts; Colorectal cancer pulmonary metastasis; Extracellular matrix; Extracellular vesicles; QSOX1

DOI:  https://doi.org/10.1016/j.canlet.2026.218645
Nature. 2026 Jun 03.

Spermine is an endogenous iron chelator that inhibits ferroptosis.

Man Li, Xuexin Yu, Shuqin Ouyang, Xiaohong Chen, Huiqi Yu, Yuanji Liu, Ziwen Li, Chunhua Yu, Rui Kang, Christine Gaillet, Ludovic Colombeau, Raphaël Rodriguez, Libing Song, Guido Kroemer, Daolin Tang, Jun Li.

Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation1. Here we identify spermine-a polyamine derived from spermidine2-as an endogenous iron chelator that directly suppresses ferroptosis. Integrating metabolomics, stable isotope tracing and biophysical studies of the interaction between spermine and Fe2+ ions, we demonstrate that aldehyde dehydrogenase 18 family member A1 (ALDH18A1) promotes an alternative glutamine-dependent pathway for de novo spermine synthesis. This process limits iron availability and lipid peroxidation in hepatocellular carcinoma. Genetic or pharmacological inhibition of ALDH18A1-through knockout, short hairpin RNA delivered using adeno-associated virus (AAV), or the small molecule inhibitor YG1702-triggers ferroptosis and impairs both spontaneous and chemically induced hepatocarcinogenesis. Conversely, supplementation of spermine protects against ferroptosis-associated ischaemia-reperfusion injury across multiple tissues, including the liver, intestine and kidneys. These findings uncover a pathophysiologically relevant metabolic circuit in which spermine-mediated iron chelation suppresses ferroptosis.

DOI: https://doi.org/10.1038/s41586-026-10597-2
Mol Cancer Ther. 2026 Jun 02.

A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter SLC43A1 (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells.

Nisha R Pawar, Heidi M Wade, Zoe Jackson, Nisha Poungpeth, Allison V Mitchell, Connor P Jewell, Dalen Chan, Pedro J Batista, Robert W Robey, Lisa M Jenkins, Michael M Gottesman.

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States, with a five-year survival rate of 65%. Oxaliplatin was the first platinum drug shown to improve CRC patient outcomes and is now a common adjuvant therapy for advanced disease, yet 90% of patients develop resistance. Oxaliplatin was developed as a third-generation derivative of cisplatin, but recent evidence points to divergent modes of action. Here, genome-wide CRISPR activation and knockout screens were conducted to identify genetic changes that confer resistance to oxaliplatin in two CRC cell lines with distinct molecular backgrounds (SW620 and RKO). Guide RNAs corresponding to the neutral amino acid transporter SLC43A1 (LAT3) were the most significantly enriched in knockout screens and depleted in activation screens, suggesting a potential role for LAT3 in modulating oxaliplatin resistance. In vitro CRISPR knockout and overexpression of LAT3 in SW620 and RKO cell lines confirm increased resistance or sensitivity to oxaliplatin, respectively. Further analysis demonstrates that increased LAT3 levels corrrelate with increased intracellular levels of oxaliplatin, and increased levels of DNA-platinum adducts and DNA damage, demonstrating that enhanced LAT3-mediated uptake of oxaliplatin can exert its expected mechanism of action and induce cytotoxicity. These findings may lead to a better understanding of oxaliplatin's mode of action in CRC and can provide new insights into the interplay between essential nutrient uptake and drug transport.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0508
bioRxiv. 2026 May 20. pii: 2026.05.19.726283. [Epub ahead of print]

Salmonella lipopolysaccharide stimulates uptake of long-chain fatty acids in the small intestine.

Eugene Koo, Gabriella Quinn, Cassie L Behrendt, Brian Hassell, Katie N Kang, Kelly A Ruhn, Gonçalo Vale, Jeffrey G McDonald, Wenhan Zhu, Sebastian E Winter, Lora V Hooper.

Enteric bacterial pathogens profoundly alter intestinal physiology during infection, yet their effects on host lipid metabolism remain poorly understood. Using mass spectrometry lipidomics, we found that infection of the mouse intestine with the bacterial pathogen Salmonella enterica serovar Typhimurium ( S . Typhimurium) stimulates uptake of long-chain fatty acids by small intestinal epithelial cells. This response coincided with increased expression of epithelial genes involved in lipid uptake and transport and required the long-chain fatty acid transporter CD36. Fatty acid uptake was triggered by S . Typhimurium lipopolysaccharide (LPS) and was impaired by bacterial mutations that alter LPS acyl chains. Mechanistically, S . Typhimurium induced lipid absorption through myeloid cell Toll-like receptor 4, a receptor for LPS. Escherichia coli , a related commensal bacterium, also induced intestinal lipid absorption through LPS, although to a lesser extent than S . Typhimurium. Finally, disruption of long-chain fatty acid absorption impaired host defense during bacterial stimulation, suggesting that bacteria-induced lipid uptake contributes to protection against enteric infection. Together, these findings identify LPS from Gram-negative intestinal bacteria as a key regulator of dietary lipid uptake by the intestinal epithelium.

DOI: https://doi.org/10.64898/2026.05.19.726283
Nat Commun. 2026 Jun 02.

Mevalonate pathway rewiring driven by enhancer remodelling confers resistance to KRAS inhibitors in colorectal cancer.

Yaoyu Guo, Yi Zhong, Peishan Hu, Yufeng Chen, Wenjun Guo, Jianfeng Chen, Peiyong Guan, Zhengran Zhou, Fang Zhu, Xian Zeng, Jiuping Gao, Qiqing Xiong, Zhaoliang Yu, Chuling Hu, Zerong Cai, Xiaoyu Xie, Jing Han Hong, Jason Yongsheng Chan, Wenyu Wang, Dechang Diao, Xiaojun Xia, Qiang Yu, Choon Kiat Ong, Yijun Gao, Xiaojian Wu, Jing Tan.

KRAS inhibitors (KRASi) have emerged as promising new cancer therapeutics for KRAS-mutant cancers; however, resistance remains a potential clinical challenge. Here, we show that reactivation of ERK is a hallmark of KRASi-resistant colorectal cancers (CRCs) and further demonstrate that enhancer remodeling rewires cholesterol biosynthesis through the mevalonate (MVA) pathway to confer this resistance. Mechanistically, enhancer remodeling activates MVA pathway, which facilitates the trafficking of KRAS to the membrane and sustains the MAPK signaling despite KRAS inhibition. Pharmacological inhibition of the MVA pathway with statins effectively blocks KRAS localization to the cell membrane, overcoming KRASi resistance in CRC. Together, these findings identify epigenetic-metabolic coupling of cholesterol biosynthesis as a mechanism of KRASi resistance and highlight targetable metabolic vulnerability in KRAS-mutant CRC.

DOI: https://doi.org/10.1038/s41467-026-73805-7
Front Genet. 2026 ;17 1869790

Editorial: Unraveling GI cancer heterogeneity through single-cell multi-omics approaches.

Rick J Jansen, Roberta Bardini, Elena Grassi.



Keywords:  GI cancers; RNA; multi-omics; single cell; spatial transcriptomics

DOI:  https://doi.org/10.3389/fgene.2026.1869790
JCI Insight. 2026 Jun 02. pii: e200275. [Epub ahead of print]

Autogenic-regenerated intestinal transplantation improves outcomes in short bowel syndrome.

Kentaro Iwaki, Takamichi Ishii, Hidenobu Kojima, Fumiaki Munekage, Hiroshi Horie, Kenta Makino, Takuma Karasuyama, Yusuke Hanabata, Elena Yukie Uebayashi, Satoshi Ogiso, Etsuro Hatano.

  Small bowel transplantation (SBT) is the only curative treatment for intestinal failure due to short bowel syndrome (SBS); however, the 10-year graft survival rate after SBT remains below 50%. Therefore, alternative treatments are required. We developed a new therapeutic strategy for intestinal failure involving in vivo intestinal regeneration using a decellularized scaffold in a rat model. A 3-cm segment of decellularized small intestine was anastomosed to the jejunum for in vivo regeneration. After four weeks of regeneration, the entire native intestine was resected to induce SBS, and the regenerated intestine was transplanted into the same rat. Histological analysis revealed regeneration of mucosa, nerves, muscular layer, and crypts, consistent with autologous cell infiltration. An indocyanine green test confirmed blood flow from the adjacent mesentery into the regenerated intestine. The regenerated intestine exhibited absorption of nutrients in vivo, and ex vivo assessments confirmed peristalsis and absorptive capacity comparable to native intestine. Transplantation of the regenerated intestine significantly improved postoperative nutritional status in SBS rats. Our method, autogenic-regenerated intestinal transplantation, showed the therapeutic potential for intestinal failure. This is the first study to demonstrate a functionally integrated regenerated intestine, providing a foundation for future regenerative therapy.

Keywords:  Development; Gastroenterology; Organ transplantation; Transplantation

DOI:  https://doi.org/10.1172/jci.insight.200275
BMC Cancer. 2026 May 30.

Single-cell transcriptome analysis reveals SOX9 mutation-driven tumor stemness and microenvironment remodeling through the COL1A1-CD44 axis in colorectal cancer.

Yuwei Pan, Xuelian Xiang, Junfeng Li, Yinggang Ge, Xiaoyan Liang.

  Colorectal cancer (CRC) exhibits substantial interpatient heterogeneity and is driven by intricate crosstalk between tumor-intrinsic mutations and the tumor microenvironment (TME), yet the mechanisms by which specific genetic alterations remodel the TME and regulate tumor stemness remain elusive. The SRY-box transcription factor 9 (SOX9) is a key regulator of intestinal homeostasis, with mutations implicated in CRC progression, but its single-cell level effects on TME dynamics have not been fully elucidated. To dissect the heterogeneity and cell-cell interactions underlying SOX9 mutation-driven CRC progression, we integrated single-cell RNA sequencing (scRNA-seq) data of 23 CRC tumor samples with bulk sequencing and mutation data from The Cancer Genome Atlas (TCGA) using the Scissor algorithm. We identified a malignant epithelial subpopulation (Scissor+) specifically associated with SOX9 mutations, which exhibits enhanced stemness signatures. Further, we predicted a significant upregulation of the COL1A1-CD44 axis in SOX9-mutant tumors via CellChat, which was supported by immunohistochemical analyses in patient tissues and mouse xenograft models. By integrating stemness-related genes and fibroblast-derived ligands, we established a 172-gene fibroblast-stemness signature that was associated with overall survival, recurrence-free survival, and disease-specific survival across multiple independent CRC cohorts. Functional validation via CD44 knockdown and in vivo xenograft assays confirmed that the COL1A1-CD44 axis mediates SOX9 mutation-driven stemness maintenance and tumor progression. Collectively, our data enhance understanding of how SOX9 mutations remodel the TME, pinpoint the COL1A1-CD44 axis as a promising therapeutic candidate for SOX9-mutant CRC, and support precise patient stratification and targeted interventions.

Keywords:  COL1A1–CD44 axis; Colorectal cancer; SOX9 mutation; Single-cell RNA sequencing; Tumor stemness

DOI:  https://doi.org/10.1186/s12885-026-16248-z
Mol Oncol. 2026 Jun 04.

Epigenetic heterogeneity and plasticity in therapy-induced tumor states through single-cell multi-omics.

Hee Jung Kim, Hwiyeong Lee, Jin Hong, Daechan Park.

  Therapeutic resistance and disease recurrence remain major unresolved challenges in oncology, primarily driven by tumor heterogeneity and the inherent plasticity of cancer cells. Although multiple biological mechanisms contribute to these processes, epigenetic mechanisms are the key regulators of clonal diversification and adaptive transcriptional reprogramming under treatment pressure. This regulatory layer operates through reversible transcriptional changes that are independent of DNA sequence alterations, enabling cancer cells to respond to a selective environment. Recent advances in analytical methodologies, particularly single-cell multi-omics approaches, have markedly improved our capacity to dissect these regulatory processes at a single-cell resolution. This review explores how diverse therapeutics, including chemotherapy, targeted agents, immunotherapy, hormonal interventions, and epigenetic drugs, induce the widespread remodeling of DNA methylation patterns, histone modifications, and chromatin accessibility. These therapy-induced molecular changes drive transitions to distinct cellular states that confer survival advantages such as drug-tolerant persister (DTP) phenotypes, senescence-like populations, epithelial-mesenchymal transition (EMT) states, and immune-evasive cell populations. We further evaluated the current single-cell multi-omics platforms for profiling chromatin-based plasticity and identifying biomarkers with direct clinical relevance. Finally, we discuss how integrative multi-layer analyses enable comprehensive characterization of tumor-state evolution, providing a conceptual framework for precision oncology strategies aimed at overcoming resistance.

Keywords:  cancer epigenetics; cell state plasticity; single‐cell multi‐omics; therapeutic resistance; tumor heterogeneity

DOI:  https://doi.org/10.1002/1878-0261.70285
J Agric Food Chem. 2026 May 31.

l-Malic Acid Enhances Intestinal Stem Cell Expansion and Barrier Function via the Sirt2/β-Catenin Signaling Pathway.

Sheng Zhang, Jiandong Lu, Hang Chen, Yaxue Lv, Siqiao Wu, Chunqi Gao.

  The continuous proliferation and differentiation of intestinal stem cells are essential for maintaining homeostasis and barrier function. l-Malic acid (L-MA), a key intermediate in host and microbial metabolism, has emerged as a potential regulator of intestinal health. In this study, oral administration of L-MA improved intestinal structure and barrier function and the activity of intestinal stem cells. Mechanistically, L-MA reduced intracellular NAD+ levels, which in turn inhibited the expression and enzymatic activity of Sirt2. This further enhanced the acetylation and activation of β-catenin, thereby upregulating the expression of ZO-1, PCNA, Occludin, and Claudin1. Using a small intestinal organoid model, we confirmed that L-MA increased organoid budding rate and formation efficiency and inhibited Sirt2 expression. In conclusion, L-MA regulates ISC expansion and improves intestinal barrier function by modulating NAD+ levels via the Sirt2/β-catenin signaling pathway. These findings provide a novel strategy for maintaining intestinal health by targeting intestinal epithelial cell homeostasis.

Keywords:  Sirt2/β-catenin; differentiation; intestinal stem cells; l-malic acid; proliferation

DOI:  https://doi.org/10.1021/acs.jafc.6c04252