bims-instec 2025-03-09 papers

bims-instec

Biomed News

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

Issue of 2025–03–09
eight papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Alterations in ether phospholipids metabolism activate the conserved UPR-Xbp1- PDIA3/ERp60 signaling to maintain intestinal homeostasis.
IL-17RA signaling provides dual tumor-suppressor function during late-stage colorectal carcinogenesis.
Coordinated differentiation of human intestinal organoids with functional enteric neurons and vasculature.
Deciphering the metabolic landscape of colorectal cancer through the lens of AhR-mediated intestinal inflammation.
Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors.
Single-cell eQTL mapping reveals cell subtype-specific genetic control and mechanism in malignant transformation of colorectal cancer.
Decoding chromosomal instability insights in CRC by integrating omics and patient-derived organoids.
3D genome landscape of primary and metastatic colorectal carcinoma reveals the regulatory mechanism of tumorigenic and metastatic gene expression.

iScience. 2025 Mar 21. 28(3): 111946

Alterations in ether phospholipids metabolism activate the conserved UPR-Xbp1- PDIA3/ERp60 signaling to maintain intestinal homeostasis.

Stephanie Makdissi, Rihab Loudhaief, Smitha George, Tabatha Weller, Minna Salim, Ahsan Malick, Yizhu Mu, Brendon D Parsons, Francesca Di Cara.

  Intestinal epithelium regeneration and homeostasis must be tightly regulated. Alteration of epithelial homeostasis is a major contributing factor to diseases such as colorectal cancer and inflammatory bowel diseases. Many pathways involved in epithelial regeneration have been identified, but more regulators remain undiscovered. Metabolism has emerged as an overlooked regulator of intestinal epithelium homeostasis. Using the model organism Drosophila melanogaster, we found that ether lipids metabolism is required to maintain intestinal epithelial homeostasis. Its dysregulation in intestinal progenitors causes the activation of the unfolded protein response of the endoplasmic reticulum (UPR) that triggers Xbp1 and upregulates the conserved disulfide isomerase PDIA3/ERp60. Activation of the Xbp1-ERp60 signaling causes Jak/Stat-mediated increase in progenitor cells, compromising epithelial barrier function and survival in males but not females. This study identified ether lipids-PDIA3/ERp60 as a key regulator of intestinal progenitor homeostasis in health that, if altered, causes pathological conditions in the intestinal epithelium.

Keywords:  Cell biology; Lipidomics; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.111946
Immunity. 2025 Feb 23. pii: S1074-7613(25)00073-1. [Epub ahead of print]

IL-17RA signaling provides dual tumor-suppressor function during late-stage colorectal carcinogenesis.

Dominic Denk, Mallika Ramakrishnan, Claire Conche, Charles Pallangyo, Marina Pesic, Fatih Ceteci, Kilian B Kennel, Asude C Kirisözü, Esther Engel, Kathleen Mohs, Birgit Ritter, Angeles Macias Pardo, Ezgi Özkurt, Falk Hildebrand, Ari Waisman, Melek C Arkan, Florian R Greten.

  Expression of interleukin (IL)-17 family cytokines is associated with tumor-promoting inflammation. We found that low expression of IL17RA associated with worse prognosis in late-stage colorectal cancer (CRC) patients. Deletion of Il17ra in intestinal epithelial cells (IECs) in a murine model of CRC enhanced epithelial-to-mesenchymal transition (EMT) via increased expression of the epidermal growth factor receptor and subsequent activation of the kinase Src. Yet, these mice were protected from metastatic disease; Il17ra deletion impaired intestinal barrier function and enhanced systemic fungal invasion and associated immunity. However, in macrophages, IL-17RA was required for spleen tyrosine kinase (Syk) activation upon fungal-induced dectin-1 engagement, and Il17ra ablation impaired IL-18 release and protective CD8+ T cell-mediated anti-tumor immunity. Combining recombinant IL-17 and heat-killed Candida albicans rendered colorectal tumors sensitive to α-PD-1 treatment in a model of microsatellite stable (MSS) CRC. Thus, IL-17RA engages two distinct tumor-suppressive mechanisms in CRC, linking EMT and fungal-induced anti-tumor immunity during tumor progression.

Keywords:  CRC; EMT; IL-17; IL-17RA; anti-tumor immunity; colon cancer; immunotherapy; inflammation; mycobiome

DOI:  https://doi.org/10.1016/j.immuni.2025.02.005
Cell Stem Cell. 2025 Feb 27. pii: S1934-5909(25)00046-3. [Epub ahead of print]

Coordinated differentiation of human intestinal organoids with functional enteric neurons and vasculature.

Charlie J Childs, Holly M Poling, Kevin Chen, Yu-Hwai Tsai, Angeline Wu, Abigail Vallie, Madeline K Eiken, Sha Huang, Caden W Sweet, Ryan Schreiner, Zhiwei Xiao, Ryan C Spencer, Samantha A Paris, Ansley S Conchola, Jonathan W Villanueva, Meghan F Anderman, Emily M Holloway, Akaljot Singh, Roman J Giger, Maxime M Mahe, Claudia Loebel, Michael A Helmrath, Katherine D Walton, Shahin Rafii, Jason R Spence.

  Human intestinal organoids (HIOs) derived from human pluripotent stem cells co-differentiate both epithelial and mesenchymal lineages in vitro but lack important cell types such as neurons, endothelial cells, and smooth muscle, which limits translational potential. Here, we demonstrate that the intestinal stem cell niche factor, EPIREGULIN (EREG), enhances HIO differentiation with epithelium, mesenchyme, enteric neuroglial populations, endothelial cells, and organized smooth muscle in a single differentiation, without the need for co-culture. When transplanted into a murine host, HIOs mature and demonstrate enteric nervous system function, undergoing peristaltic-like contractions indicative of a functional neuromuscular unit. HIOs also form functional vasculature, demonstrated in vitro using microfluidic devices and in vivo following transplantation, where HIO endothelial cells anastomose with host vasculature. These complex HIOs represent a transformative tool for translational research in the human gut and can be used to interrogate complex diseases as well as for testing therapeutic interventions with high fidelity to human pathophysiology.

Keywords:  HIO; directed differentiation; enteric neruon; human intestinal organoids; intestine; organoids; pluripotent; stem cells; vasculature

DOI:  https://doi.org/10.1016/j.stem.2025.02.007
Discov Oncol. 2025 Mar 07. 16(1): 275

Deciphering the metabolic landscape of colorectal cancer through the lens of AhR-mediated intestinal inflammation.

Jasmine Swain, Preeti, Chandana Mohanty, Atul Anand Bajoria, Srinivas Patnaik, Aoife Ward Gahlawat, Kumar Nikhil, Soumya R Mohapatra.

  Colorectal cancer (CRC) ranks as the third most common cancer worldwide, with its incidence steadily increasing due to an aging demographic and various lifestyle-related risk factors, including poor nutrition, tobacco use, sedentary behaviour and obesity. These factors promote the risk of colorectal cancer by inducing chronic colonic inflammation, a principal catalyst of carcinogenesis. This review delves into evidence that suggests that metabolic abnormalities mediated through inflammatory responses are fundamental in the progression of CRC. This dysregulation of essential metabolic pathways in colorectal cancer, facilitates tumor proliferation, immune evasion, and metastasis. Additionally, this review explores how inflammatory mediators, and dietary carcinogens induce metabolic alterations, fostering a pro-tumorigenic milieu. Special focus is placed on the aryl hydrocarbon receptor (AhR) as a pivotal metabolic regulator that links inflammation and tumor metabolism, elucidating its function in the reconfiguration of cellular energetics and the inflammatory microenvironment. Furthermore, this review also focuses on clarifying the relationship between inflammation, metabolic dysregulation, and the progression of CRC, so as to identify potential therapeutic targets.

Keywords:  Aryl hydrocarbon receptor (AhR); Colorectal cancer (CRC); Inflammation; Metabolic mediators; Tryptophan

DOI:  https://doi.org/10.1007/s12672-025-01949-x
Nat Commun. 2025 Mar 04. 16(1): 2197

Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors.

Céline Patte, Roxane M Pommier, Anthony Ferrari, Felicia Fei-Lei Chung, Maria Ouzounova, Pauline Moullé, Mathieu Richaud, Rita Khoueiry, Maëva Hervieu, Silvia Breusa, Marion Allio, Nicolas Rama, Laura Gérard, Valérie Hervieu, Gilles Poncet, Tanguy Fenouil, Vincent Cahais, Anne-Sophie Sertier, Anne Boland, Delphine Bacq-Daian, Benjamin Ducarouge, Julien C Marie, Jean-François Deleuze, Alain Viari, Jean-Yves Scoazec, Colette Roche, Patrick Mehlen, Thomas Walter, Benjamin Gibert.

Small intestinal neuroendocrine tumors (siNETs) are rare bowel tumors arising from malignant enteroendocrine cells, which normally regulate digestion throughout the intestine. Though infrequent, their incidence is rising through better diagnosis, fostering research into their origin and treatment. To date, siNETs are considered to be a single entity and are clinically treated as such. Here, by performing a multi-omics analysis of siNETs, we unveil four distinct molecular groups with strong clinical relevance and provide a resource to study their origin and clinical features. Transcriptomic, genetic and DNA methylation profiles identify two groups linked to distinct enteroendocrine differentiation patterns, another with a strong immune phenotype, and the last with mesenchymal properties. This latter subtype displays the worst prognosis and resistance to treatments in line with infiltration of cancer-associated fibroblasts. These data provide insights into the origin and diversity of these rare diseases, in the hope of improving clinical research into their management.

DOI: https://doi.org/10.1038/s41467-025-57305-8
Cancer Discov. 2025 Mar 04.

Single-cell eQTL mapping reveals cell subtype-specific genetic control and mechanism in malignant transformation of colorectal cancer.

Can Chen, Yimin Cai, Wenlong Hu, Kai Tan, Zequn Lu, Xuanyu Zhu, Ziying Liu, Chunyi He, Guangping Xu, Ruizhe Zhang, Caibo Ning, Shuheng Ruan, Jiayan Gao, Xiaojun Yang, Yongchang Wei, Xu Zhu, Xiangpan Li, Faxi Wang, Fubing Wang, Jiaoyuan Li, Meng Jin, Bin Li, Ying Zhu, Jianbo Tian, Xiaoping Miao.

Colorectal cancer (CRC) is a heterogeneous disease that develops through a stepwise accumulation, yet the underlying mechanisms at single-cell resolution remain unclear. Here, we profiled 751,531 single-cell transcriptomes, spatial transcriptomics, and snMultiomes from 142 multistage samples, revealing the cellular and molecular alterations and dynamic intercellular crosstalk during CRC development. Additionally, we created a CRC sc-eQTL map identifying 16,833 significant pairs across 28 cell subtypes, with over 76% of sc-eQTLs being cell-type-specific and fewer than 15% detectable in bulk datasets. A polygenic risk score (PRS) derived from sc-eQTLs substantially improved CRC risk prediction. We prioritized rs4794979 that is associated with an increased CRC risk (OR=1.11, P=2.04×10-12) by promoting LGALS9 expression mediated by ELK1. Elevated LGALS9 in epithelia interacts with SLC1A5 on fibroblasts, promoting transformation into cancer-associated fibroblasts (CAFs), simultaneously induces CD8+ T cells exhaustion via LGALS9-TIM3 axis, thereby facilitating CRC development. Blocking LGALS9-TIM3 axis enhanced anti-PD-1 therapy to inhibit CRC progression.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1561
J Exp Clin Cancer Res. 2025 Feb 28. 44(1): 77

Decoding chromosomal instability insights in CRC by integrating omics and patient-derived organoids.

Federica Papaccio, Manuel Cabeza-Segura, Blanca García-Micó, Francisco Gimeno-Valiente, Sheila Zúñiga-Trejos, Valentina Gambardella, María Fernanda Gutiérrez-Bravo, Carolina Martinez-Ciarpaglini, Pilar Rentero-Garrido, Tania Fleitas, Susana Roselló, Juan Antonio Carbonell-Asins, Marisol Huerta, David Moro-Valdezate, Desamparados Roda, Noelia Tarazona, Manuel M Sánchez Del Pino, Andrés Cervantes, Josefa Castillo.

   BACKGROUND: Chromosomal instability (CIN) is involved in about 70% of colorectal cancers (CRCs) and is associated with poor prognosis and drug resistance. From a clinical perspective, a better knowledge of these tumour's biology will help to guide therapeutic strategies more effectively.
METHODS: We used high-density chromosomal microarray analysis to evaluate CIN level of patient-derived organoids (PDOs) and their original mCRC tissues. We integrated the RNA-seq and mass spectrometry-based proteomics data from PDOs in a functional interaction network to identify the significantly dysregulated processes in CIN. This was followed by a proteome-wGII Pearson correlation analysis and an in silico validation of main findings using functional genomic databases and patient-tissues datasets to prioritize the high-confidence CIN features.
RESULTS: By applying the weighted Genome Instability Index (wGII) to identify CIN, we classified PDOs and demonstrated a good correlation with tissues. Multi-omics analysis showed that our organoids recapitulated genomic, transcriptomic and proteomic CIN features of independent tissues cohorts. Thanks to proteotranscriptomics, we uncovered significant associations between mitochondrial metabolism and epithelial-mesenchymal transition in CIN CRC PDOs. Correlating PDOs wGII with protein abundance, we identified a subset of proteins significantly correlated with CIN. Co-localisation analysis in PDOs strengthened the putative role of IPO7 and YAP, and, through in silico analysis, we found that some of the targets give significant dependencies in cell lines with CIN compatible status.
CONCLUSIONS: We first demonstrated that PDO models are a faithful reflection of CIN tissues at the genetic and phenotypic level. Our new findings prioritize a subset of genes and molecular processes putatively required to cope with the burden on cellular fitness imposed by CIN and associated with disease aggressiveness.

Keywords:  Chromosomal instability; Colorectal cancer; Mass spectrometry-based proteomics; Multi-omics; Patient-derived organoids

DOI:  https://doi.org/10.1186/s13046-025-03308-8
Commun Biol. 2025 Mar 04. 8(1): 365

3D genome landscape of primary and metastatic colorectal carcinoma reveals the regulatory mechanism of tumorigenic and metastatic gene expression.

Xiang Xu, Jingbo Gan, Zhaoya Gao, Ruifeng Li, Dandan Huang, Lin Lin, Yawen Luo, Qian Yang, Jingxuan Xu, Yaru Li, Qing Fang, Ting Peng, Yaqi Wang, Zihan Xu, An Huang, Haopeng Hong, Fuming Lei, Wensheng Huang, Jianjun Leng, Tingting Li, Xiaochen Bo, Hebing Chen, Cheng Li, Jin Gu.

Colorectal carcinoma (CRC) is a deadly cancer with an aggressive nature, and how CRC tumor cells manage to translocate and proliferate in a new tissue environment remains not fully understood. Recently, higher-order chromatin structures and spatial genome organization are increasingly implicated in diseases including cancer, but in-depth studies of three-dimensional genome (3D genome) of metastatic cancer are currently lacking, preventing the understanding of the roles of genome organization during metastasis. Here we perform multi-omics profiling of matched normal colon, primary tumor, lymph node metastasis, liver metastasis and normal liver tissue from CRC patients using Hi-C, ATAC-seq and RNA-seq technologies. We find that widespread alteration of 3D chromatin structure is accompanied by dysregulation of genes including SPP1 during the tumorigenesis or metastasis of CRC. Remarkably, the hierarchy of topological associating domain (TAD) changes dynamically, which challenges the traditional view that the TAD structure between tumor and normal tissue is conservative. In addition, we define compartment stability score to measure large-scale alteration in metastatic tumors. To integrate multi-omics data and recognize candidate genes driving cancer metastasis, a pipeline is developed based on Hi-C, RNA-seq and ATAC-seq data. And three candidate genes ARL4C, FLNA, and RGCC are validated to be associated with CRC cell migration and invasion using in vitro knockout experiments. Overall, these data resources and results offer new insights into the involvement of 3D genome in cancer metastasis.

DOI: https://doi.org/10.1038/s42003-025-07647-2