bims-gerecp 2025-06-15 papers

bims-gerecp

Biomed News

on Gene regulatory networks of epithelial cell plasticity

Issue of 2025–06–15
seven papers selected by
Xiao Qin, University of Oxford

Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm.
Unbiased profiling of multipotency landscapes reveals spatial modulators of clonal fate biases.
Innate immunity of the gut epithelium: Blowing in the WNT?
Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis.
Dissecting crosstalk induced by cell-cell communication using single-cell transcriptomic data.
Novel colorectal cancer screening methods - opportunities and challenges.
Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.

Cancer Res. 2025 Jun 11.

Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm.

Erica A Oliveira, Salvatore Milite, Javier Fernandez-Mateos, George D Cresswell, Erika Yara-Romero, Georgios Vlachogiannis, Bingjie Chen, Chela T James, Lucrezia Patruno, Gianluca Ascolani, Ahmet Acar, Timon Heide, Inmaculada Spiteri, Alex Graudenzi, Giulio Caravagna, Andrea Bertotti, Trevor A Graham, Luca Magnani, Nicola Valeri, Andrea Sottoriva.

Cancer drug resistance is multi-factorial, driven by heritable (epi)genetic changes but also phenotypic plasticity. Here, we dissected drivers of resistance by perturbing colorectal cancer patient-derived organoids longitudinally with drugs in sequence. Combined longitudinal lineage tracking, single cell multi-omics analysis, evolutionary modelling, and machine learning revealed that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences. The cellular memory of drug resistance was encoded as a heritable epigenetic configuration from which multiple transcriptional programs could run, supporting a one-to-many (epi)genotype-to-phenotype map that explains how clonal expansions and plasticity manifest together. This epigenetic landscape may ensure drug resistant subclones can exhibit distinct phenotypes in changing environments while still preserving the cellular memory encoding for their selective advantage. Chemotherapy resistance was instead entirely driven by transient phenotypic plasticity rather than stable clonal selection. Inducing further chromosomal instability before drug application changed clonal evolution but not convergent transcriptional programs. Collectively, these data show how genetic and epigenetic alterations are selected to engender a "permissive epigenome" that enables phenotypic plasticity.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0999
bioRxiv. 2025 Jun 06. pii: 2024.11.15.623687. [Epub ahead of print]

Unbiased profiling of multipotency landscapes reveals spatial modulators of clonal fate biases.

Alek G Erickson, Sergey Isaev, Artem Artemov, Jingyan He, Bettina Semsch, Aliia Murtazina, Jia Sun, Katrin Mangold, Anthi Chalou, Jonas Frisen, Michael Ratz, Emma Andersson, Peter V Kharchenko, Igor Adameyko.

Embryogenesis is commonly viewed through a tree model of cell differentiation, which fails to capture the spatiotemporal modulation of cell multipotency underlying morphogenesis. In this study we profile the multipotency landscape of the embryo, using in vivo single-cell clonal lineage tracing of mouse embryos traced from neurulation until mid-gestation, combined with a machine learning tool that categorizes individual clones into lineages based on shared transcriptional context. This revealed a previously unrecognized continuous, embryo-wide gradient of clonal fate biases, in which anatomical position and clonal composition are mutually predictive. Comparing clonal lineages revealed gene regulatory networks underlying the dynamic biasing of cells towards specific fates by spatial transcription factor programs. However, mosaic combinatorial perturbations targeting the Hedgehog pathway generated clones in which positional identity was mismatched with clonal composition, demonstrating that extrinsic signals can override the axial patterning system underlying clonal fate biases. Altogether, our work demonstrates an effective practical approach for dissecting mechanisms of lineage specification and has implications for stem cell engineering.

DOI: https://doi.org/10.1101/2024.11.15.623687
Mucosal Immunol. 2025 Jun 10. pii: S1933-0219(25)00064-9. [Epub ahead of print]

Innate immunity of the gut epithelium: Blowing in the WNT?

Maaike H de Vries, Ewart W Kuijk, Edward E S Nieuwenhuis.

  Intestinal epithelial cells need to be able to launch a quick and adequate immune response against pathogens, while tolerating commensals. This delicate balance requires a tight control over the activation of the NFκB and Interferon pathways to prevent chronic inflammation. Simultaneously, intestinal stem cell maintenance and differentiation are strictly regulated by the WNT/β-catenin and Bone Morphogenetic Protein signaling pathways to allow proper tissue homeostasis. There is emerging evidence that these cell identity and innate immunity pathways are molecularly intertwined, which may have implications for our mechanistic understanding of intestinal diseases such as inflammatory bowel disease and colorectal cancer. Here, we provide a comprehensive overview of the most important molecular interactions between these pathways. We identify the current gaps in our knowledge, and we propose promising areas for future research, in particular organoid research combined with single cell sequencing technologies.

Keywords:  BMP; Crosstalk; Immune response; Intestinal epithelium; WNT/β-catenin

DOI:  https://doi.org/10.1016/j.mucimm.2025.06.004
bioRxiv. 2025 Jun 01. pii: 2025.05.28.656689. [Epub ahead of print]

Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis.

Adrien Grimont, David J Falvo, Whitney J Sisso, Paul Zumbo, Christopher W Chan, Francisco Santos, Grace Pan, Megan Cleveland, Tomer M Yaron, Alexa Osterhoudt, Yinuo Meng, Maria Paz Zafra, William B Fall, Andre F Rendeiro, Erika Hissong, Rhonda K Yantiss, Doron Betel, Mark A Magnuson, Steven D Leach, Anil K Rustgi, Lukas E Dow, Rohit Chandwani.

Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic cancer (PDAC). How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement novel Ptf1a-TdTomato mice and multiple KRAS mutants across an array of genetic, pharmacologic, and inflammatory perturbations in vivo . Whereas KRAS G12D co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRAS G12R/V can initiate but not sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. We find the KRAS G12R/V defects consist of a failure to invoke robust EGFR signaling and activate Rac1/Vav1, with constitutive Akt activation in vivo sufficient to rescue the tumorigenic potential of KRAS G12R . As the marked heterogeneity among KRAS variants begins early in tumorigenesis, these data are crucial to understanding mutation-specific oncogenic trajectories and directing the implementation of KRAS -directed therapeutics.
SIGNIFICANCE: Defining how KRAS mutants drive distinct outcomes in human pancreatic cancer is critical for developing allele-specific therapeutic approaches. This study unveils a hierarchy among KRAS G12D , KRAS G12V , and KRAS G12R to drive tumor initiation, owing to heterogeneous activation of EGFR, PI3K/AKT, and RAC1 signaling, thus revealing mutation-specific evolutionary paths in pancreatic tumorigenesis.

DOI: https://doi.org/10.1101/2025.05.28.656689
bioRxiv. 2025 Jun 03. pii: 2025.05.31.657197. [Epub ahead of print]

Dissecting crosstalk induced by cell-cell communication using single-cell transcriptomic data.

Jiawen Hou, Wei Zhao, Qing Nie.

During cell-cell communication (CCC), pathways activated by different ligand-receptor pairs may have crosstalk with each other. While multiple methods have been developed to infer CCC networks and their downstream response using single-cell RNA-seq data (scRNA-seq), the potential crosstalk between pathways connecting CCC with its downstream targets has been ignored. Here we introduce a machine learning-based method SigXTalk to analyze the crosstalk using scRNA-seq data by quantifying signal fidelity and specificity, two critical quantities measuring the effect of crosstalk. Specifically, a hypergraph learning method is used to encode the higher-order relations among receptors, transcription factors and target genes within regulatory pathways. Benchmarking of SigXTalk using simulation data shows the effectiveness, robustness, and accuracy in identifying key shared molecules among crosstalk pathways and their roles in transferring shared CCC information. Analysis of disease data shows SigXTalk's capability in identifying crucial signals, targets, regulatory networks, and CCC patterns that distinguish different disease conditions. Applications to the data with multiple time points reveals SigXTalk's capability in tracking the evolution of crosstalk pathways over time. Together our studies provide a systematic analysis of CCC-induced regulatory networks from the perspective of crosstalk between pathways.

DOI: https://doi.org/10.1101/2025.05.31.657197
Nat Rev Clin Oncol. 2025 Jun 06.

Novel colorectal cancer screening methods - opportunities and challenges.

Melina A McCabe, Anthony J Mauro, Robert E Schoen.

Globally, colorectal cancer (CRC) is the second leading cause of cancer death and the third most common incident cancer. CRC begins as adenomatous or serrated polyps, and in particular as advanced precursor lesions (APLs), which have the potential to progress into invasive cancers. Screening for CRC facilitates early detection and can identify cancers more amenable to cure, and can also detect and remove precursor lesions, thus also preventing CRC. Colonoscopy is the mainstay of screening in the USA and has the distinct advantage of enabling both detection and removal of precursors lesions. However, colonoscopy is burdensome, expensive and invasive, and often has negative findings. Non-invasive tests, such as testing stool samples for biomarkers of risk, have the potential to identify individuals who are more likely to benefit from colonoscopy. From a public health perspective, improving compliance with screening remains a priority. Technological innovations, including the emergence of new markers to improve stool testing and the development of blood tests that examine cell-free DNA have the potential to improve screening uptake and effectiveness. The trade-off between uptake of screening testing, detection of cancer and important precursor lesions such as APLs, and costs make for a complex calculus. In this Review, we describe the current state of CRC screening and evaluate the risks and benefits of new developments in screening.

DOI: https://doi.org/10.1038/s41571-025-01037-7
bioRxiv. 2025 Jun 07. pii: 2025.06.06.658169. [Epub ahead of print]

Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.

Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Johanna Ten Hoeve, Kevin J Williams, Tolga Sever, Isabela Fuentes, Ömer H Yilmaz.

Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state, and cellular dynamics. In the gastrointestinal tract, obesogenic high-fat diets enhance intestinal stem cell activity and tumorigenesis. However, the impact of ketogenic diets (KD), which contain even higher lipid content but induce ketogenesis, remains poorly understood. This is particularly relevant for patients with familial adenomatous polyposis (FAP), who face a high risk of small intestinal tumours. Here, we combine dietary, genetic, and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone body production. Through genetic manipulation of the ketogenic pathway, we modulate local and systemic ketone body production; however, neither inhibition nor augmentation of the ketogenic enzyme HMGCS2 nor disruption of ketolysis altered tumour progression. In contrast, inhibition of fatty acid oxidation did limit adenomatous formation. These findings reveal that dietary lipid content, through FAO rather than ketone body metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.

DOI: https://doi.org/10.1101/2025.06.06.658169