Identification of a targetable ST2-expressing fibroblast subset driving Peutz-Jeghers syndrome polyposis DOI Open Access
Eva Domènech‐Moreno, Wei‐Wen Lim,

Anders Brandt

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 30, 2023

Abstract Peutz-Jeghers syndrome (PJS) is associated with early-onset and recurring gastrointestinal hamartomatous polyposis caused by hereditary inactivating mutations in the tumor suppressor gene LKB1 (STK11). Due to lack of efficient prophylactic therapies PJS patients require regular surgical interventions have an increased risk cancer. LKB1-deficient fibroblasts been identified as drivers polyposis, but a safely druggable target remains be identified. Here we investigate tumorigenic mechanisms polyps using single-cell RNA sequencing predisposed tissue ST2-expressing crypt top fibroblast (CTF) cluster enriched polyps. The relevance CTFs was supported fast following deletion Lkb1 CTFs. transcriptional signature characterizing ST2+ (ST2-CTFs) inflammation-associated fibroblasts, exacerbated inflammation. Cell-cell communication analysis ST2-CTF interleukin 11 (IL-11) upstream regulator ST2-CTFs, consistently, reprogramming toward ST2 vitro dependent on IL-11. Importantly, neutralizing IL-11 antibody efficiently reduced burden mouse model. In summary, our results reveal identify key mediator potential therapeutic PJS.

Language: Английский

Activation of fetal-like molecular programs during regeneration in the intestine and beyond DOI
Sara Viragova, Dong Li,

Ophir D Klein

et al.

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(7), P. 949 - 960

Published: July 1, 2024

Language: Английский

Citations

13
Stromal Niche Signals That Orchestrate Intestinal Regeneration DOI Creative Commons
Helen E. Abud, Shanika L. Amarasinghe, Diana Micati

et al.

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2024, Volume and Issue: 17(5), P. 679 - 685

Published: Jan. 1, 2024

Stromal cell populations have a central role in providing signals that support the maintenance, differentiation, and function of intestinal epithelium. The behavior fate epithelial cells is directed by spatial organization stromal either sustain stem progenitor identity or drive differentiation. A combination single-cell analyses, mouse models, organoid coculture assays provided insight into diversity delivered cells. Signaling gradients are established fine-tuned expression signaling agonists antagonists along crypt-villus axis. On injury, there disruptions to abundance populations. There also distinct changes originating from these impact remodeling How coordinate mediate repair tissue injury inflammatory bowel diseases beginning emerge. Understanding processes may lead opportunities target as strategy modify disease states.

Language: Английский

Citations

4
Dark force rising: Reawakening and targeting of fetal-like stem cells in colorectal cancer DOI Creative Commons
Sigrid K. Fey,

Nuria Vaquero‐Siguero,

René Jackstadt

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(6), P. 114270 - 114270

Published: May 23, 2024

Stem cells play pivotal roles in maintaining intestinal homeostasis, orchestrating regeneration, and key steps of colorectal cancer (CRC) initiation progression. Intriguingly, adult stem are reduced during many these processes. On the contrary, primitive fetal programs, commonly detected development, emerge tissue repair, CRC metastasis, therapy resistance. Recent findings indicate a dynamic continuum between cell programs. We discuss critical mechanisms facilitating plasticity states highlight heterogeneity observed upon appearance fetal-like states. focus on therapeutic opportunities that arise by targeting how those concepts can be translated into clinic.

Language: Английский

Citations

4
Interleukin‐11 expressed in the polyp‐enriched fibroblast subset is a potential therapeutic target in Peutz‐Jeghers syndrome DOI Open Access
Eva Domènech‐Moreno, Wei‐Wen Lim,

Melissa G Montrose

et al.

The Journal of Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Abstract Peutz‐Jeghers syndrome (PJS) is associated with early‐onset gastrointestinal polyposis caused by hereditary inactivating pathogenic variants in the tumor suppressor gene STK11 ( LKB1 ). Due to lack of prophylactic therapies, management PJS polyps requires frequent surveillance. Interestingly, studies mouse models have revealed that stromal cells drive polyp formation, but detailed understanding cell types and interactions involved has been lacking. Using single‐cell RNA sequencing model polyps, we here identify a polyp‐enriched crypt top fibroblast (pCTF) cluster characterized transcriptional signature also enriched patient polyps. The pCTF was noted primary fibroblasts vitro following acute loss. Targeted deletion Stk11 using Foxl1 ‐ Cre led upregulation genes later polyposis. pCTFs displayed similarity inflammation‐associated fibroblasts, exacerbated inflammation. Cell–cell communication analysis identified interleukin 11 (IL‐11) as potential inducer, consistent this, IL‐11 required for reprogramming toward Importantly, neutralizing antibody efficiently reduced formation indicating key, targetable role development. Together results characterize subset key mediator therapeutic target PJS. © 2025 Pathological Society Great Britain Ireland.

Language: Английский

Citations

0
Muc6-expressing gastric isthmus progenitors contribute to regeneration and metaplasia supported by myeloid-mesenchymal interactions DOI Creative Commons

Junya Arai,

Yusuke Iwata, Ayumu Tsubosaka

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Summary Gastric mucosal homeostasis is maintained by tissue-resident stem and progenitor cells residing in the isthmus region. Following injury, surviving contribute to regeneration, coinciding with characteristic pathological changes such as atrophic gastritis metaplasia. To comprehensively understand cellular dynamics involved this process, we performed single-cell spatial transcriptomics using newly generated transgenic mice. In human samples mouse models, loss of gastric chief precedes, even induces, parietal during progression atrophy metaplasia, validating causal relationship underlying decrease these two lineages. Single-cell analysis confirmed robust stemness metaplastic Muc6 -expressing neck lineage following either or cell ablation, lineage-tracing experiments revealed that progenitors serve a source metaplasia regeneration. Mechanistically, injury recruits IL-1-expressing myeloid cells, which stimulates NRG1 production stromal fibroblasts, leading proliferation regeneration mediated Myc activation progenitors. These findings highlight injury-responsible cell-like function isthmal progenitors, play critical role disease progression. Visual abstract

Language: Английский

Citations

0
E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma DOI Creative Commons
Ludivine Bertonnier‐Brouty, Jonas Andersson, Tuomas Kaprio

et al.

Cancer Medicine, Journal Year: 2024, Volume and Issue: 13(9)

Published: April 30, 2024

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs. Objective Using similarities between tumor development and normal embryonic development, which accompanied by rapid cell expansion, we aimed characterize signaling pathways that were reinitiated during formation expansion. Methods Results Here, report transcription factors E2F1 E2F8 are potential key regulators PDAC. RNA expression mainly localized proliferating cells developing pancreas malignant Silencing PANC‐1 pancreatic inhibited proliferation impaired spreading migration. Moreover, loss also affected viability apoptosis E2F PDAC tissues correlating mitosis pathway genes, suggesting promote cycle regulation tumorigenesis cells. Conclusion Our findings illustrate expressed progenitor cells, where they contribute expansion proliferation, viability, migration making these genes attractive therapeutic prognostic markers for cancer.

Language: Английский

Citations

2
Single-cell resolution of intestinal regeneration in pythons without crypts illuminates conserved vertebrate regenerative mechanisms DOI Creative Commons
Aundrea K. Westfall, Siddharth S. Gopalan, Jarren Kay

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(43)

Published: Oct. 18, 2024

Canonical models of intestinal regeneration emphasize the critical role crypt stem cell niche to generate enterocytes that migrate villus ends. Burmese pythons possess extreme regenerative capacity yet lack crypts, thus providing opportunities identify noncanonical but potentially conserved mechanisms expand our understanding in vertebrates, including humans. Here, we leverage single-nucleus RNA sequencing fasted and postprandial python small intestine signaling pathways cell–cell interactions underlying python’s response. We find entails activation multiple growth stress response, core lipid metabolism unfolded protein response enterocytes. Our single-cell resolution highlights extensive heterogeneity mesenchymal population intercellular communication directs major tissue restructuring shift out a dormant state by activating both embryonic developmental wound healing pathways. also distinct roles BEST4+ coordinating key transitions via NOTCH signaling. Python shares features molecules with mammalian gastric bypass, indicating programs are common both. findings provide different insights into cooperative vertebrates independent crypts which have been otherwise obscured model species where temporal phases generative limited development or recovery from injury.

Language: Английский

Citations

1
Regionalized cell and gene signatures govern esophageal epithelial homeostasis DOI Creative Commons
David Grommisch, Harald Lund, Evelien Eenjes

et al.

Developmental Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

Citations

1
The Signaling of Neuregulin-Epidermal Growth Factor Receptors and Its Impact on the Nervous System DOI Creative Commons

Marzia Tagliaferro,

Donatella Ponti

Neuroglia, Journal Year: 2023, Volume and Issue: 4(4), P. 253 - 274

Published: Oct. 13, 2023

The activation of members the Epidermal Growth Factor Receptor (EGFR) family (including ErbB) triggers pathways that have significant effects on cellular processes and profound consequences both in physiological pathological conditions. Within nervous system, neuregulin (NRG)/ErbB3 signaling plays a crucial role promoting formation maturation excitatory synapses. Noteworthy is ErbB3, which actively involved process cerebellar lamination myelination. All ErbB-family, particular been observed within nuclei various cell types, including full-length receptors alternative variants. One these variants was detected Schwann cells glioblastoma primary where it showed neuregulin-dependent expression. It binds to promoters’ chromatin associated with genes, like ezrin, Ranvier’s node. Its nucleolar localization suggests may play ribosome biogenesis proliferation. regulation ErbB3 expression complex dynamic can be influenced by different factors, miRNAs. This mechanism appears often poor prognosis. Altogether, targeting has emerged as an active area research treatment. These findings highlight underappreciated receptor potentially pivotal diverse pathologies, implying existence shared intricate warrants further investigation.

Language: Английский

Citations

2
Regionalized cell and gene signatures govern oesophageal epithelial homeostasis DOI Creative Commons
David Grommisch, Harald Lund, Evelien Eenjes

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 21, 2024

Abstract Regionalized disease prevalence is a common feature of the gastrointestinal tract. Herein, we employed regionally resolved Smart-seq3 single-cell sequencing, generating comprehensive cell atlas adult mouse oesophagus. Characterizing oesophageal axis, unveil non-uniform distribution epithelial basal cells, fibroblasts and immune cells. In addition, reveal position-dependent, but subpopulation-independent, transcriptional signature, collectively regionalized landscape. Combining in vivo models with organoid co-cultures, demonstrate that proximal distal progenitor states are functionally distinct. We find more permissive for growth compared to profile two dimensions, where proximal-distal epithelial-stromal gradients impact maintenance. Finally, predict verify how WNT-, BMP-, IGF-and NRG-signalling differentially engaged along axis. establish cellular framework understanding regionalization, providing functional basis susceptibility.

Language: Английский

Citations

0