bims-instec 2025-07-20 papers

bims-instec

Biomed News

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

Issue of 2025–07–20
thirteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.
Cetuximab increases LGR5 expression and augments LGR5-targeting antibody-drug conjugate efficacy in patient-derived colorectal cancer models.
Modeling oxaliplatin resistance in colorectal cancer reveals a SERPINE1-based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype.
GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells.
IRE1α and IRE1β Protect Intestinal Epithelium and Suppress Colorectal Tumorigenesis through Distinct Mechanisms.
Unbiased recording of clonal potency reveals species-specific regulation of mammalian intestine.
Recent evolution of the developing human intestine affects metabolic and barrier functions.
Bacterial ADP-heptose triggers stem cell regeneration in the intestinal epithelium following injury.
Alternative splicing factor RAB3IP as a novel risk signature to predict the prognosis of colorectal cancer.
Targeting SIRT2 induces MLH1 deficiency and boosts antitumor immunity in preclinical colorectal cancer models.
Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics.
Unraveling SREBF1's role in elevating colorectal cancer prognosis through proliferation and migration inhibition.
Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.

Nat Metab. 2025 Jul 14.

Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.

Simon Andersson, Hien Bui, Arto Viitanen, Daniel Borshagovski, Ella Salminen, Sami Kilpinen, Angelika Gebhart, Emilia Kuuluvainen, Swetha Gopalakrishnan, Nina Peltokangas, Martyn James, Kaia Achim, Eija Jokitalo, Petri Auvinen, Ville Hietakangas, Pekka Katajisto.

Cellular metabolism is a key regulator of cell fate1, raising the possibility that the recently discovered metabolic heterogeneity between newly synthesized and chronologically old organelles may affect stem cell fate in tissues2,3. In the small intestine, intestinal stem cells (ISCs)4 produce metabolically distinct progeny5, including their Paneth cell (PC) niche6. Here we show that asymmetric cell division of mouse ISCs generates a subset enriched for old mitochondria (ISCmito-O), which are metabolically distinct, and form organoids independently of niche because of their ability to recreate the PC niche. ISCmito-O mitochondria produce more α-ketoglutarate, driving ten-eleven translocation-mediated epigenetic changes that promote PC formation. In vivo α-ketoglutarate supplementation enhanced PC turnover and niche renewal, aiding recovery from chemotherapy-induced damage in aged mice. Our results reveal a subpopulation of ISCs whose old mitochondria metabolically regulate cell fate, and provide proof of principle for metabolically promoted replacement of specific aged cell types in vivo.

DOI: https://doi.org/10.1038/s42255-025-01325-7
bioRxiv. 2025 Jun 24. pii: 2025.06.18.660406. [Epub ahead of print]

Cetuximab increases LGR5 expression and augments LGR5-targeting antibody-drug conjugate efficacy in patient-derived colorectal cancer models.

Peyton C High, Zhengdong Liang, Cara Guernsey-Biddle, Shraddha Subramanian, Yueh-Ming Shyu, Adela M Aldana, Yukimatsu Toh, Kendra S Carmon.

Colorectal cancer (CRC) remains the second-leading cause of cancer-associated deaths, indicating an urgent need for improved therapeutic options. We previously generated antibody-drug conjugates (ADCs) targeting the cancer stem-like cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). However, tumor relapse due to LGR5 downregulation and suboptimal payload selection warranted strategies to improve ADC efficacy. Here we report cetuximab, an EGFR-targeting monoclonal antibody indicated for RAS WT metastatic CRC, augments LGR5 expression independent of RAS/PIK3CA mutation status and promotes EGFR-LGR5 interactions. Furthermore, we describe the development of LGR5 ADCs incorporating a camptothecin-derived payload that is well-tolerated and significantly inhibits tumor growth. Importantly, cetuximab in combination with LGR5 ADCs results in enhanced tumor inhibition or regression versus single-agent treatment and extends survival in RAS MUT patient-derived xenografts. These findings support growing evidence that ADC combination therapies may be more effective than monotherapies and suggests a broader clinical use for cetuximab in treating RAS MUT CRC.

DOI: https://doi.org/10.1101/2025.06.18.660406
Cell Death Dis. 2025 Jul 16. 16(1): 529

Modeling oxaliplatin resistance in colorectal cancer reveals a SERPINE1-based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype.

Stephen Qi Rong Wong, Mohua Das, Kenzom Tenzin, Niranjan Shirgaonkar, Huiwen Chua, Lin Xuan Chee, Ahpa Sae Yeoh, Astley Aruna Murugiah, Wei Yong Chua, Madelaine Skolastika Theardy, Ethan Jadon Subel, Matan Thangavelu Thangavelu, Jane Vin Chan, Choon Kong Yap, Iain Bee Huat Tan, Petros Tsantoulis, Sabine Tejpar, Jia Min Loo, Ramanuj DasGupta.

Drug resistance and distant metastases are leading causes of mortality in colorectal cancer (CRC), yet the molecular mechanisms linking these processes remain elusive. In this study, we demonstrate that acquired resistance to oxaliplatin, a first-line chemotherapeutic in CRC, enhances metastatic potential through transcriptional reprogramming. Using a clinically relevant dosing regimen, we generated oxaliplatin-resistant CRC cells that displayed increased metastatic potential. Integrated transcriptomic and phenotypic analyses revealed that dysregulated cholesterol biogenesis amplifies TGF-β signaling, which in turn drives expression of SERPINE1, which serves as a key effector of both oxaliplatin resistance and metastasis. Furthermore, we uncovered a SERPINE1-associated nine-gene expression signature, RESIST-M, that robustly predicts overall and relapse-free survival across distinct patient cohorts. Notably, RESIST-M stratifies a high-risk subtype of CMS4/iCMS3-fibrotic patients that display the poorest prognosis, underscoring its clinical relevance. Targeting of SERPINE1 or cholesterol biosynthesis re-sensitized resistant, pro-metastatic cells to oxaliplatin in mouse xenograft models. Altogether, this study uncovers a mechanistic link between metabolic rewiring and transcriptional plasticity underlying therapy-induced metastasis in primary CRC. Additionally, it also reveals actionable vulnerabilities that offer both prognostic value and therapeutic potential.

DOI: https://doi.org/10.1038/s41419-025-07855-y
Oncogenesis. 2025 Jul 13. 14(1): 25

GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells.

Le Zhang, Lidia Atencia Taboada, Selami Baglamis, Maartje de Kroon, Carolien Elshout, Prashanthi Ramesh, Roxan F C P A Helderman, Arezo Torang, Kate Cameron, Milou S van Driel, Valérie M Wouters, Sanne M van Neerven, Jan Paul Medema.

BCL-XL is a crucial anti-apoptotic protein that supports survival of intestinal cells during the progression and in established colorectal cancer (CRC). While targeting BCL-XL with BH3 mimetics is effective, its significant toxicity highlights the need for alternative approaches. Importantly, the early steps in intestinal transformation are marked by a competition between normal and transformed stem cells in which the mutant cells gain a supercompetitive advantage due to the secretion of WNT inhibitors. Using multiple human and murine CRC models, we revealed that GSK-3 inhibition strongly sensitized to BH3 mimetic-induced killing. As expected, GSK-3 inhibition significantly upregulated the WNT pathway, but also led to marked enhancement of BH3 mimetic-induced apoptosis, as measured by mitochondrial BAX aggregation, Caspase-3 activation and Propidium Iodide exclusion. Furthermore, GSK-3 inhibition provided an advantage to wild-type intestinal organoids in competition with APC-mutant counterparts due to reactivation of the WNT pathway. More strikingly, combining GSK-3 and BCL-XL inhibition profoundly affected the supercompetition APC-mutant intestinal cells exert over the wild-types. In effect, the combination therapy enhanced the competitive fitness of wild-type cells and resulted in the killing of APC-mutant organoids, pointing to a novel combination therapy that can be further exploited in the treatment of adenomas and CRC.

DOI: https://doi.org/10.1038/s41389-025-00569-y
bioRxiv. 2025 May 07. pii: 2025.05.01.651751. [Epub ahead of print]

IRE1α and IRE1β Protect Intestinal Epithelium and Suppress Colorectal Tumorigenesis through Distinct Mechanisms.

Ruishu Deng, Miao Wang, Thanyarat Promlek, Clementine Druelle-Cedano, Rabi Murad, Nicholas O Davidson, Randal J Kaufman.

Intestinal epithelial cells (IECs) uniquely express two IRE1 paralogues, IRE1α and IRE1β, whose roles in intestinal physiology are incompletely understood. We examined the individual and cooperative functions of IRE1α and IRE1β in IECs using mice using intestine-specific deletion of Ire1α or germline Ire1β deletion, and subsequently with double deleted Ire1α, Ire1β mice. At baseline, intestine-specific Ire1α deleted mice and mice with germline Ire1β deletion exhibited no morphologic changes in small intestine or colon, but double deleted Ire1α -/- Ire1β -/- mice developed progressive intestinal and colonic injury and tumorigenesis. In contrast to single-deleted IECs, RNA-Seq from Ire1α -/- Ire1β -/- IECs revealed decreased expression of defense-associated mRNAs, together with increased expression of inflammatory and pathogenic mRNAs. Utilizing orthogonal models of intestinal tumorigenesis, reflecting either inflammatory-mutagenic injury (AOM-DSS) or spontaneous polyposis (APC min ), we observed that loss of either intestinal epithelial Ire1α or of Ire1β alone produced a growth advantage, increasing tumor burden. IRE1α mediated splicing of Xbp1 mRNA was maintained following Ire1β deletion but not in double deleted Ire1α -/- Ire1β -/- mice. Increased expression of either Ire1α or Ire1β mRNA was associated with improved survival in patients with colorectal cancer. Taken together our findings suggest IRE1 paralogues utilize essential but distinct mechanisms to safeguard intestinal homeostasis and suppress tumorigenesis.

DOI: https://doi.org/10.1101/2025.05.01.651751
bioRxiv. 2025 Jun 12. pii: 2025.06.10.658707. [Epub ahead of print]

Unbiased recording of clonal potency reveals species-specific regulation of mammalian intestine.

Mirazul Islam, Matthew E Bechard, Yilin Yang, Alan J Simmons, Yanwen Xu, James N Higginbotham, Ping Zhao, Zheng Cao, Naila Tasneem, Sarah E Glass, Nicholas O Markham, Frank Revetta, Marisol A Ramirez-Solano, Qi Liu, Jeffrey L Franklin, Ken S Lau, Robert J Coffey.

The mammalian intestine regenerates rapidly after damage, yet the clonal dynamics and species-specific regulation of different populations remain poorly understood. Here we used synthetic or naturally occurring DNA alterations to reconstruct clonal histories of the mouse and human intestinal epithelium at single-cell resolution. In mice, we uncovered the clonal architecture of different cell types and their roles in regeneration, supporting a hierarchical regenerative response model. We identified a rare embryonic precursor population that persisted in the adult and was crucial for regeneration after irradiation. This population was marked by Tob2, which is required for nuclear transport of Ascl2. A parallel clonal analysis of 65 human colonic biopsies revealed secretory lineage bias and an age-associated decline in clonal diversity in the distal colon. Unlike highly proliferative murine Lgr5+ stem cells, human LGR5+ cells were found largely quiescent, revealing species-specific difference in clonal potency, and suggesting a distinct regulation of intestinal stemness.

DOI: https://doi.org/10.1101/2025.06.10.658707
Science. 2025 Jul 17. eadr8628

Recent evolution of the developing human intestine affects metabolic and barrier functions.

Qianhui Yu, Umut Kilik, Stefano Secchia, Lukas Adam, Yu-Hwai Tsai, Christiana Fauci, Jasper Janssens, Charlie J Childs, Katherine D Walton, Rubén López-Sandoval, Angeline Wu, Marina Almató Bellavista, Sha Huang, Calen A Steiner, Yannick Throm, Michael James Boyle, Zhisong He, Joep Beumer, Barbara Treutlein, Craig B Lowe, Jason R Spence, J Gray Camp.

Diet, microbiota, and other exposures place the intestinal epithelium as a nexus for evolutionary change; however, little is known about genomic changes associated with adaptation to a uniquely human environment. Here, we interrogate the evolution of cell types in the developing human intestine by comparing tissue and organoids from humans, chimpanzees, and mice. We find that recent changes in primates are associated with immune barrier function and lipid/xenobiotic metabolism, and that human-specific genetic features impact these functions. Enhancer assays, genetic deletion, and in silico mutagenesis resolve evolutionarily significant enhancers of Lactase (LCT) and Insulin-like Growth Factor Binding Protein 2 (IGFBP2). Altogether, we identify the developing human intestinal epithelium as a rapidly evolving system, and show that great ape organoids provide insight into human biology.

DOI: https://doi.org/10.1126/science.adr8628
Cell Stem Cell. 2025 Jul 04. pii: S1934-5909(25)00231-0. [Epub ahead of print]

Bacterial ADP-heptose triggers stem cell regeneration in the intestinal epithelium following injury.

Shawn Goyal, Cynthia X Guo, Ojas Singh, Adrienne Ranger, Caitlin F Harrigan, Justin Meade, Alexander Luchak, Derek K Tsang, Herbert Y Gaisano, Nan Gao, Scott A Yuzwa, Jeffrey L Wrana, Dana J Philpott, Scott D Gray-Owen, Stephen E Girardin.

  ADP-heptose (ADP-Hep), a metabolite produced by gram-negative bacteria, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the function of ALPK1-TIFA signaling in primary cells and in physiological settings remains poorly understood. Here, we showed that, in the intestinal epithelium, ALPK1 and TIFA were mainly expressed by the intestinal stem cell (ISC) pool, where they controlled the replacement of homeostatic ISCs by new revival stem cells (revSCs) following injury. Mechanistically, ADP-Hep triggered pro-inflammatory nuclear factor κB (NF-κB) signaling and tumor necrosis factor (TNF)-dependent ISC apoptosis, which initiated a transforming growth factor β (TGF-β)- and YAP-dependent revSC program. Single-cell transcriptomics and lineage-tracing experiments identified Paneth cells as a cell of origin for revSC induction in response to ADP-Hep. In vivo, revSC emergence following irradiation or dextran-sodium-sulfate-induced injury was blunted in Tifa-/- mice. Together, our work reveals that ALPK1-TIFA signaling contributes to ISC turnover in response to bacterial detection in the intestine.

Keywords:  Alpk1; CLU; Tifa; innate immunity; intestine; regeneration; revival stem cell

DOI:  https://doi.org/10.1016/j.stem.2025.06.009
J Cancer. 2025 ;16(9): 2959-2969

Alternative splicing factor RAB3IP as a novel risk signature to predict the prognosis of colorectal cancer.

Zhengwei Zhou, Fei Gao, Han Lei, Haixuan Wen, Jiaxi Tang, Yulong Peng, Lili Fan, Lu Xu, Guang Shu.

  Emerging evidence suggests that aberrant alternative splicing plays a vital role in the development of tumors. However, the expression of splicing factors (SF) in colorectal cancer and its relationship with prognosis is still unclear. Here, we divided patients into high-risk and low-risk groups through univariate COX analysis and LASSO regression analysis, and selected 13 alternative splicing factors that are highly correlated with prognosis for subsequent analysis. We systematically analyzed the prognostic value of transcription levels of SFs in colorectal cancer (CRC) and found that RAB3A interacting protein (RAB3IP), programmed cell death 4 (PDCD4), golgin B1 (GOLGB1), and neuregulin 4 (NRG4) as the most predictive markers for the prognosis of CRC. After comparing the expression of four splicing factors in cancer tissues with normal tissues as well as OS analysis, it is strongly indicated that only RAB3IP demonstrates a significant positive correlation with favorable prognosis. Accordingly, we established a risk signature of transcription levels of RAB3IP as an independent prognostic marker for CRC. Moreover, by the Gene Set Enrichment Analysis (GSEA), we demonstrated that the RAB3IP was correlated to Cell Cycle, WNT pathway and Spliceosome in cancer. In conclusion, our findings demonstrate that SFs play a critical role in CRC pathogenesis, and identify RAB3IP as a novel prognostic biomarker for CRC.

Keywords:  alternative splicing; colorectal cancer; metastasis.; prognosis; splicing factor

DOI:  https://doi.org/10.7150/jca.110271
Sci Transl Med. 2025 Jul 16. 17(807): eadv0766

Targeting SIRT2 induces MLH1 deficiency and boosts antitumor immunity in preclinical colorectal cancer models.

Qianling Gao, Lanlan Yang, Shubiao Ye, Mingru Mai, Yiting Liu, Xuefei Jiang, Xingzhi Feng, Zihuan Yang.

Low tumor mutation burden and an immunosuppressive tumor microenvironment (TME) of colorectal cancers (CRCs) contribute to resistance to immune-checkpoint inhibitors in patients. Understanding the mechanisms of cancer immune evasion will be helpful to develop new therapeutic strategies. Here, leveraging mass spectrometry-based proteomic profiling data and clinical validation, we identified that low sirtuin 2 (SIRT2) expression was associated with improved prognosis and an immune-active TME in CRC. Specifically, genetic knockdown or pharmacological inhibition of SIRT2 resulted in enhanced infiltration and cytotoxicity of CD8+ T cells, leading to tumor regression across multiple CRC mouse models and patient-derived organoids. Further in vitro experimental analysis demonstrated that SIRT2 interacted with and deacetylated MutL protein homolog 1 (MLH1) at Lys402/443/461, thereby preventing MLH1 ubiquitination and degradation. SIRT2 knockdown or inhibition down-regulated MLH1, increasing DNA damage and activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. In addition, both in vivo and in vitro experiments indicated that SIRT2 inhibition stimulated the production of tumor neoantigens and enhanced major histocompatibility complex class I (MHC-I) expression, reprogramming the TME toward an immune-active status and inducing long-lasting immune memory. Last, a combination strategy using SIRT2 inhibitor 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) and anti-programmed cell death protein-1 (PD-1) therapy enhanced immune response, making tumors susceptible to immunotherapy and driving substantial tumor regression in vivo. Our study uncovers a role of SIRT2 in reprogramming TME and underscores the potential of targeting SIRT2 to sensitize CRC to immunotherapy.

DOI: https://doi.org/10.1126/scitranslmed.adv0766
bioRxiv. 2025 Jun 24. pii: 2022.10.02.508492. [Epub ahead of print]

Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics.

Inbal Avraham-Davidi, Simon Mages, Johanna Klughammer, Noa Moriel, Shinya Imada, Matan Hofree, Evan Murray, Jonathan Chen, Karin Pelka, Arnav Mehta, Genevieve M Boland, Toni Delorey, Leah Caplan, Danielle Dionne, Robert Strasser, Jana Lalakova, Anezka Niesnerova, Hao Xu, Morgane Rouault, Itay Tirosh, Nir Hacohen, Fei Chen, Omer Yilmaz, Jatin Roper, Orit Rozenblatt-Rosen, Mor Nitzan, Aviv Regev.

While advances in single cell genomics have helped to chart the cellular components of tumor ecosystems, it has been more challenging to characterize their specific spatial organization and functional interactions. Here, we combine single cell RNA-seq, spatial transcriptomics by Slide-seq, and in situ multiplex RNA analysis, to create a detailed spatial map of healthy and dysplastic colon cellular ecosystems and their association with disease progression. We profiled inducible genetic CRC mouse models that recapitulate key features of human CRC, assigned cell types and epithelial expression programs to spatial tissue locations in tumors, and computationally used them to identify the regional features spanning different cells in the same spatial niche. We find that tumors were organized in cellular neighborhoods, each with a distinct composition of cell subtypes, expression programs, and local cellular interactions. Comparing to scRNA-seq and Slide-seq data from human CRC, we find that both cell composition and layout features were conserved between the species, with mouse neighborhoods correlating with malignancy and clinical outcome in human patient tumors, highlighting the relevance of our findings to human disease. Our work offers a comprehensive framework that is applicable across various tissues, tumors, and disease conditions, with tools for the extrapolation of findings from experimental mouse models to human diseases.

DOI: https://doi.org/10.1101/2022.10.02.508492
PLoS One. 2025 ;20(7): e0327503

Unraveling SREBF1's role in elevating colorectal cancer prognosis through proliferation and migration inhibition.

Dongling Li, Qinrui Cai, Fan Xu, Ling Lin, Xiaoya Zhou, Li Li, Yao Chen, Tianlin Feng, Yuanxiu Gan, Chenhua Zhang, Fan Yang.

Sterol Regulatory Element-Binding Protein 1 (SREBF1), a central regulator of lipid metabolism, has unclear pan-cancer roles and clinical implications. This study integrated various databases and functional experiments to systematically investigate the heterogeneous characteristics of SREBF1 across cancers. Pan-cancer analysis revealed significant upregulation of SREBF1 in multiple cancer types, including colorectal cancer (CRC). Survival analysis demonstrated that SREBF1 overexpression serves as an independent risk factor for poor prognosis in colorectal cancer patients. Focusing on CRC, functional studies revealed that SREBF1 drives tumor progression by enhancing cancer cell proliferation and migration, while its knockdown induces cell cycle arrest and apoptosis in HCT116 cells. Mechanistically, SREBF1 is implicated in lipid metabolic reprogramming and interacts with the tumor immune microenvironment, also with genetic alterations. This study highlights the regulatory role of SREBF1 in pan-cancer contexts and provides novel insights into its potential as a prognostic biomarker and therapeutic target, particularly in colorectal cancer.

DOI: https://doi.org/10.1371/journal.pone.0327503
bioRxiv. 2025 May 10. pii: 2025.05.09.653205. [Epub ahead of print]

Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.

Sarah M Chang, Muhammad Bin Munim, Sonia E Trojan, Anna Shevzov-Zebrun, Keene L Abbott, Matthew G Vander Heiden.

The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can also increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affects cancer cell proliferation.

DOI: https://doi.org/10.1101/2025.05.09.653205