bims-instec 2026-08-02 papers

bims-instec

Biomed News

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

Issue of 2026–08–02
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Co-targeting deregulated WNT and MAPK signaling pathways limits phenotypic reprogramming of intestinal stem cell progeny in KRAS hyperactivated colorectal cancer.
Live-Cell Imaging and Single-Cell Tracking to Monitor Clonal Dynamics and Fate Transitions in Human and Murine Intestinal Organoids.
Golgi organization regulates stem cell function in the small intestine.
Obesity-driven microbial GABA depletion promotes metabolic rewiring and colorectal cancer progression.
Mapping micrometastatic seeds of relapse.
Intestinal stem cells count self-renewal divisions to switch multipotency.
Cancer stem cells are hyper-responsive sensors of the tumour microenvironment and regulate metastasis dynamics through YAP/TAZ.
The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
Translational Recoding in Tumors.
Metastasis-associated DNA methylation alterations persist after accounting for immune and stromal cell heterogeneity in primary colorectal tumors.

Cancer Res. 2026 Jul 28.

Co-targeting deregulated WNT and MAPK signaling pathways limits phenotypic reprogramming of intestinal stem cell progeny in KRAS hyperactivated colorectal cancer.

Silvia Palladino, Rona Yaeger.

In their recent paper, Moore and colleagues demonstrate that, upon KRAS hyperactivation, colorectal cancer (CRC) growth is driven by a reprogramming of Lrg5+ intestinal stem cells progeny towards the acquisition of a regenerative phenotype. They find that this phenotype is regulated by a balance between WNT-related intestinal stem cell and MAPK-related regenerative and proliferative transcriptional programs. By targeting both pathways, they are able to suppress this dynamic plasticity and achieve tumor regression in cell line and mouse models. The antagonistic relationship between these central pathways defined here provides key insight into genomic patterns of CRC and targeted therapy strategies.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-3173
J Vis Exp. 2026 Jul 10.

Live-Cell Imaging and Single-Cell Tracking to Monitor Clonal Dynamics and Fate Transitions in Human and Murine Intestinal Organoids.

Xuan Zheng, Daniel Krueger, Johan H van Es, Hans Clevers.

The intestinal epithelium undergoes rapid self-renewal through stem cell division, cell differentiation, and migration. Understanding how individual cells commit to specific fates and how clonal dynamics emerge within this tissue requires methods that capture cellular behavior in real time and at single-cell resolution. Intestinal organoids recapitulate key features of epithelial self-organization and cell-type diversity, making them a powerful system for studying these processes in a controlled setting. Here we present a protocol for long-term confocal live-cell imaging (up to 72 h) and single-cell tracking in human and murine intestinal organoids, built around two complementary reporter strategies. First, we describe the generation of mosaic organoids by combining differentially labeled cell populations, enabling single-cell resolution of membrane-localized and cytoskeletal reporters that cannot otherwise be attributed to individual cells in a dense epithelium. Second, we use cell-type-specific fate reporters (MUC2 for goblet cells and DEFA5 for Paneth cells) to monitor secretory cell type transitions in real time. The protocol covers organoid culture, mosaic organoid formation, sample preparation with strategies to minimize phototoxicity, image acquisition over several days, and semi-automated single-cell tracking using OrganoidTracker, which reconstructs cell trajectories and lineages over time. While demonstrated in intestinal organoids, this framework is readily adaptable to other epithelial organoid systems, including gastric, pancreatic, and colonic models, broadening its utility for studies of epithelial biology, homeostasis, and disease.

DOI: https://doi.org/10.3791/72058
Nat Commun. 2026 Jul 29. pii: 7606. [Epub ahead of print]17(1):

Golgi organization regulates stem cell function in the small intestine.

Ilya Belevich, Lucas Porcile, Agustin Sola-Carvajal, David Grommisch, Karl Annusvar, Paul Heinz, Srustidhar Das, Anna T Webb, Simon Andersson, Nalle Pentinmikko, Eduardo J Villablanca, James R Goldenring, Maria Kasper, Eija Jokitalo, Robert J Coffey, Pekka Katajisto, Sandra Scharaw.

Cell-to-cell signaling between niche and stem cells regulates tissue renewal. While the identity of many mediating factors is known, it is largely unknown whether stem cells optimize their receptiveness to niche signals according to the niche organization. Here, we show that Lgr5+ small intestinal stem cells (ISCs) regulate the morphology and orientation of their secretory apparatus to match the niche architecture, and to increase transport efficiency of niche signal receptors. ISCs orient their Golgi apparatus laterally towards Paneth cells of the epithelial niche, and divide Golgi into multiple stacks. Stem cells with multiple lateral Golgi transport stem cell receptors with a higher efficiency than cells with one single Golgi. The lateral Golgi orientation and enhanced receptor transport requires A-kinase anchor protein 9 (Akap9), and is necessary for normal renewal capacity. Moreover, reduced Akap9 in aged ISCs renders ISCs insensitive to niche-dependent modulation of Golgi stack number and transport efficiency. Our results reveal a stem cell-specific Golgi complex configuration that facilitates efficient niche signal reception and tissue renewal, which is compromised in the aged epithelium.

DOI: https://doi.org/10.1038/s41467-026-75679-1
Nat Commun. 2026 07 27. pii: 7404. [Epub ahead of print]17(1):

Obesity-driven microbial GABA depletion promotes metabolic rewiring and colorectal cancer progression.

Wei Guo, Kaiyue Sun, Xia Wang, Mengmeng Li, Zheng Li, Xizan Yue, Yi Yin, Tengfei Ma, Yikun Li, Xiaoning Xu, Jianbo Liu, Jiahao Zhang, Cuiyu Zhang, Panpan Feng, Ruijie Ma, Jiayi Ren, Jie Liu, Changan Liu, Xiang Gao, Dawei Chen, Jingxin Li.

Obesity is a major risk factor for colorectal cancer (CRC), yet the mechanisms linking obesity-associated gut dysbiosis to tumor progression remain unclear. Here, we show that a high-fat diet and fecal microbiota from patients with obesity-associated CRC deplete the GABA-producing commensal Bacteroides ovatus, resulting in reduced luminal GABA and accelerated tumorigenesis. Microbial GABA activates epithelial GABAB receptor signaling and induces TPI1 through the PI3K-HIF1α pathway. Increased TPI1-derived glyceraldehyde-3-phosphate inhibits PPP1CA, maintains YAP phosphorylation, restricts nuclear YAP activity, and suppresses pentose phosphate pathway flux, thereby limiting tumor growth. Consistently, obesity-associated CRC exhibits reduced fecal GABA, decreased TPI1 expression, and metabolic rewiring. A GABA-deficient B. ovatus mutant fails to restore GABA or suppress tumors despite normal colonization, whereas oral GABA supplementation or recolonization with wild-type B. ovatus markedly reduces tumor burden. These findings identify a microbiota-neurotransmitter-metabolism axis linking obesity to CRC and suggest microbiota-based GABA restoration as a potential preventive strategy.

DOI: https://doi.org/10.1038/s41467-026-76079-1
Cancer Cell. 2026 Jul 31. pii: S1535-6108(26)00345-4. [Epub ahead of print]

Mapping micrometastatic seeds of relapse.

Hui Ting Grace Yeo, Iain Beehuat Tan.

In this issue of Cancer Cell, Liu et al. apply spatial multi-omics to map colorectal cancer micrometastases across primary tumors and matched liver and lung metastases, revealing liver micrometastases as an early evolved, stem-like, immune-suppressed residual disease state linked to a six-gene recurrence signature.

DOI: https://doi.org/10.1016/j.ccell.2026.07.007
Nature. 2026 Jul 29.

Intestinal stem cells count self-renewal divisions to switch multipotency.

Dong Tong, Anqi Li, Quanquan Jiang, Qili Yuan, Xiaozhao Liu, Ximiao He, Jiejunyi Liang, Yunyun Han, Zheng Guo.

Multipotent stem cells maintain tissue homeostasis by producing distinct daughter cell types in defined proportions1,2, but how they coordinate type-specific ratios during repeated divisions remains unknown. Drosophila intestinal stem cells (ISCs) switch between producing enteroendocrine cells (EECs) and enterocytes (ECs)3,4, yet maintain a constant EEC:EC ratio despite rapid tissue turnover5-7. Here we show that ISCs intrinsically count self-renewal divisions through an epigenetic mechanism to control multipotency switching. After each asymmetrical division producing an enteroendocrine mother cell (EMC; which divides symmetrically to produce a pair of EECs), ISCs execute precisely eight divisions that generate ECs, before switching back to EMC production at the ninth division. This counting is driven by antagonistic histone modifications: Trithorax group (TrxG)-dependent active marks (H3K4me3 and H3K36me3) progressively decline, whereas Polycomb group (PcG)-dependent repressive marks (H3K27me3) accumulate over successive divisions, triggering fate switching at a threshold. The division count is tunable by modulating TrxG and PcG activities, but withstands acute injury. Crucially, EMC-derived transient Notch signalling establishes active marks in ISCs to initiate the count, designating each EMC production as the cycle's start point. Our work identifies a histone-modification-based division counter that programs developmental fidelity in stem cells, with implications for engineered tissue growth and differentiation disorder therapies.

DOI: https://doi.org/10.1038/s41586-026-10814-y
Nat Cell Biol. 2026 Jul 27.

Cancer stem cells are hyper-responsive sensors of the tumour microenvironment and regulate metastasis dynamics through YAP/TAZ.

Binwu Tang, Jacob Minin, Victoria M Gonzalez, Zoya Z Khan, Andrew R Gaines, Yuval Raviv, Yu-An Yang, Christine P Carney, Zachary G Millman, Daniel Grun, Cristiana M Pineda, Alina Sharma, Dominic Esposito, Hualong Yan, Jing Huang, Andy D Tran, Michael Kruhlak, Howard H Yang, Maxwell P Lee, Lalage M Wakefield.

Cancer stem cells (CSCs) drive metastasis and therapy resistance, yet their behaviour within the complex tumour microenvironment remains poorly understood. Here we use a fluorescent reporter that marks CSCs to show that CSCs and their more differentiated progeny display strikingly different population dynamics during metastatic lung colonization in breast cancer models. CSC expansion is rapidly curtailed early in colonization, suggesting a strong negative feedback mechanism acting selectively on this subpopulation. We showed that CSCs are exceptionally sensitive to local microenvironmental cues such as cell crowding and nutrient availability. They respond earlier and more extensively than their differentiated progeny, thereby coupling tumour growth to resource and space availability. Microenvironmental signals converge on the transcriptional regulatory complex YAP/TAZ/TEAD, with CSC sensitivity arising from elevated signal reception and greater chromatin accessibility at TEAD-regulated enhancers. Targeting upstream inputs to this pathway reversed chemotherapy-induced CSC enrichment in lung metastases, suggesting a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41556-026-02013-8
Nat Aging. 2026 Jul 30.

The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.

Aidan R Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Alexander Tom, Hui Wang, Katarzyna M Kedziora, Adam Chatoff, Andrea Andress Huacachino, Mariola M Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar Tangudu, Emily Noonan, Jeff Danielson, Miho Naruse, Amal Taher Elhaw, Sierra White, Danyang Li, Callen T Wallace, Frederick Keeney, Felicia Lazure, Esther Elishaev, Lauren Borho, Hope A Townsend, Robin D Dowell, Aaron Clauset, Dorota E Jazwinska, Matthew S Laird, Huda Atiya, Denarda Dangaj, Lan G Coffman, George Tseng, Steffi Oesterreich, Andrew Kossenkov, Qin Liu, Ana P Gomes, Aditi U Gurkar, Francisco J Schopfer, Francesmary Modugno, Simon C Watkins, Ioannis K Zervantonakis, Benjamin G Bitler, Wayne Stallaert, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.

Cellular senescence is a consequence of many chemotherapeutics that plays context-dependent roles in cancer. Senescent cells secrete an array of factors collectively known as the senescence-associated secretory phenotype (SASP). Here we show that the cisplatin-induced SASP enhances the detachment of high-grade serous ovarian cancer (HGSOC) cells in vitro and dissemination in vivo. We identify fructose as a metabolic component of the SASP that facilitates cell detachment and show that a high-fructose diet increases HGSOC dissemination in vivo. We identified complex I as the driver of SASP-mediated cell detachment and HGSOC dissemination. Mechanistically, this effect was driven by SASP-mediated inhibition of an NAD+-SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. These findings reveal that the SASP reprograms the metabolic microenvironment, promoting metastatic dissemination in a paracrine fashion, and highlight a pro-tumorigenic metabolic effect of fructose in the SASP that may contribute to the high recurrence rate of HGSOC.

DOI: https://doi.org/10.1038/s43587-026-01172-5
Cold Spring Harb Perspect Biol. 2026 Jul 29. pii: a041869. [Epub ahead of print]

Translational Recoding in Tumors.

Chen Weller, Osnat Bartok, Panagiotis Poulis, Yardena Samuels.

Protein synthesis is tightly regulated in cells; however, in cancer, ribosomes deviate from canonical translation, generating altered protein products. These deviations arise from cell-intrinsic alterations, as well as extrinsic pressures within the tumor microenvironment, collectively reshaping the translational landscape and reducing translation fidelity. Translational recoding in cancer expands proteome diversity and promotes tumor fitness by enhancing stress adaptation, metabolic, and phenotypic plasticity. At the same time, recoding events generate peptides that are often presented as tumor-specific antigens, thereby eliciting immune responses against cancer. Accordingly, therapeutic strategies that modulate translational fidelity and induce recoding are emerging to enhance tumor immunogenicity and improve immunotherapy responses. Here, we examine the drivers and consequences of translational recoding in cancer, its dual role in promoting tumor adaptation while shaping immune surveillance, and its potential as a targetable vulnerability in cancer therapy.

DOI: https://doi.org/10.1101/cshperspect.a041869
Res Sq. 2026 Jul 14. pii: rs.3.rs-9657747. [Epub ahead of print]

Metastasis-associated DNA methylation alterations persist after accounting for immune and stromal cell heterogeneity in primary colorectal tumors.

Alos B Diallo, Sabin D Hart, John P Zavras, Scott M Palisoul, Fred W Kolling, Louis J Vaickus, Jiaoyuan E Sun, Lucas A Salas, Brock C Christensen, Joshua J Levy.

   Background: Metastatic colorectal cancer (CRC) remains a major cause of cancer mortality, yet how epigenetic states within the tumor microenvironment (TME) relate to metastatic progression has not been fully characterized. Although aberrant DNA methylation has been implicated in cancer progression, many studies do not account for immune and stromal cell composition, which can confound bulk methylation analyses. We sought to define DNA methylation patterns in primary colorectal tumors associated with lymph node and distant metastasis, while accounting for tumor microenvironment cellular composition.
Methods: We analyzed DNA methylation patterns from 57 patients with stage pT3 colorectal adenocarcinoma, comparing tumors with and without concurrent metastasis. Methylation cytometry deconvolution was performed to estimate immune, stromal, and tumor cell fractions. Differentially methylated positions associated with metastatic status were identified using covariate-adjusted epigenome-wide association analyses, with genomic context enrichment to assess regional methylation patterns. Genomic context enrichment and gene annotations were used to assess biological relevance. Methylation-expression correlations were assessed in an independent TCGA-COAD cohort to evaluate whether discovery loci correspond to differences in gene expression.
Results: Metastatic status was not associated with large-scale differences in inferred cellular composition. Epigenome-wide analyses identified hypomethylated loci mapped to genes involved in Wnt/β-catenin and PI3K/Akt signaling, epithelial-mesenchymal transition, and immune modulation, whereas hypermethylated loci tracked to genes related to adhesion, Wnt signaling, cytoskeletal organization, and interferon signaling. Genomic context enrichment revealed CpG island enrichment among hypermethylated DMPs in the distant metastasis contrast. Among metastasis-associated CpGs, 23 showed significant negative correlations between methylation and gene expression in TCGA-COAD (FDR < 0.05), predominantly at promoter-proximal CpG islands, supporting a relationship between promoter methylation and reduced gene expression. Two candidate CpGs showed directional concordance with significance in matched TCGA contrasts.
Conclusions: We identify distinct epigenetic alterations associated with metastatic progression in colorectal cancer that are largely independent of bulk immune and stromal composition. Integration of methylation-expression data supports a role for promoter hypermethylation in metastasis-associated gene silencing. These findings highlight potential methylation-based biomarkers of metastatic risk and may inform future precision oncology strategies in CRC.

Keywords:  DNA Methylation; colorectal cancer; epigenetics; epigenomewide association study; tumor microenvironment

DOI:  https://doi.org/10.21203/rs.3.rs-9657747/v1