Biology subjects

WANG, T. C.

Publications and source records attributed to WANG, T. C..

7 recordsLinked to original sources

bioRxiv2026

Progastrin activates colonic fibroblasts and induces a paracrine pro-migratory program in colorectal cancer cells

PurposeProgastrin, aberrantly expressed in colorectal cancer (CRC), is an established trophic factor for tumour epithelial cells. Whether it also promotes CRC progression by reprogramming stromal fibroblasts remains unclear. We investigated progastrin-induced colonic fibroblast activation and its functional consequences on CRC cell migration. MethodsFibroblast activation was assessed in the colonic mucosa of hGAS mice and in the human normal colonic fibroblast line CCD18Co exposed to synthetic progastrin. The impact of tumour-derived progastrin on epithelial cell motility was analysed using HCT116 cells expressing a control shRNA (shLuc) or a progastrin-targeting shRNA (shPG) in transwell migration assays performed with or without fibroblasts. Candidate paracrine mediators were evaluated by RT-qPCR, ELISA and neutralization experiments, and signalling was interrogated using the PI3K inhibitor LY294002. ResultsColonic fibroblasts from hGAS mice displayed stromal FAP and SMA expression, indicating fibroblast activation in vivo. In CCD18Co cells, progastrin increased FAP and SMA protein levels. Fibroblasts enhanced HCT116 cell migration. This effect was stronger when tumour cells expressed progastrin or when fibroblasts were preconditioned by progastrin-producing HCT116 cells. Progastrin induced CXCL12/SDF-1 and CXCL8/IL-8 expression and secretion by fibroblasts, and neutralization of either chemokine abrogated the additional migratory effect conferred by progastrin-activated fibroblasts. Progastrin triggered sustained Akt phosphorylation in fibroblasts, while PI3K inhibition suppressed CXCL12 and CXCL8 secretion and abolished fibroblast-dependent tumour cell migration. ConclusionThese data identify a stromal dimension of progastrin signalling in CRC and support a model in which tumour-derived progastrin activates colonic fibroblasts and elicits a PI3K/Akt-dependent paracrine programme that enhances CRC cell migration.

cancer biology↗

bioRxiv2025

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

Gastric mucosal homeostasis is maintained by tissue-resident stem and progenitor cells residing in the isthmus region. Following mucosal injury, surviving cells contribute to regeneration, coinciding with characteristic pathological changes such as atrophic gastritis and metaplasia. To comprehensively understand the cellular dynamics involved in this process, we performed single-cell and spatial transcriptomics using newly generated transgenic mice. In human samples and mouse models, loss of gastric chief cells precedes, and even induces, loss of parietal cells during the progression of atrophy and metaplasia, validating the causal relationship underlying the decrease of these two lineages. Single-cell analysis confirmed robust stemness and metaplastic changes in the Muc6-expressing neck lineage following either chief or parietal cell ablation, and lineage-tracing experiments revealed that Muc6-expressing isthmus progenitors serve as a source of metaplasia and regeneration. Mechanistically, mucosal injury recruits IL-1-expressing myeloid cells, which stimulates NRG1 production in stromal fibroblasts, leading to mucosal proliferation and regeneration mediated by Myc activation in isthmus progenitors. These findings highlight the injury-responsible stem cell-like function of Muc6-expressing isthmal progenitors, which play a critical role in mucosal homeostasis and disease progression. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/648856v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@10fc2eaorg.highwire.dtl.DTLVardef@1c5b82corg.highwire.dtl.DTLVardef@1be747dorg.highwire.dtl.DTLVardef@d1d722_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Knowledge Discovery in Datasets of Proteomics by Systems Modeling in Translational Research on Pancreatic Cancer

Knowledge discovery in databases (KDD) can contribute to translational research, also known as translational medicine, by bridging the gap between in vitro and in vivo studies and clinical applications. Here, we propose a systems modeling workflow for KDD. This framework includes data collection of composition model (various research models) and processing model (proteomics) and analytical model (bioinformatics, artificial intelligence/machine leaning and pattern evaluation), knowledge presentation, and feedback loops for hypothesis generation and validation. We applied this workflow to study pancreatic ductal adenocarcinoma (PDAC). Through this approach, we identified the common proteins between human PDAC and various research models in vitro (cells, spheroids and organoids) and in vivo (mouse mice). Accordingly, we hypothesized potential translational targets on hub proteins and the related signaling pathways, PDAC specific proteins and signature pathways, and high topological proteins. Thus, we suggest that this systems modeling workflow can be a valuable method for KDD, facilitating knowledge discovery in translational targets in general and in particular to PADA in this case.

systems biology↗

bioRxiv2025

Niche-driven phenotypic plasticity and cis-regulatory dynamics of a revised model for intestinal secretory differentiation

HIGHLIGHTSO_LIDelineation of chromatin and mRNA dynamics of intestinal secretory differentiation C_LIO_LIPaneth cells have few unique enhancers and share mRNAs and TFs with goblet cells C_LIO_LIUnlike other secretory derivatives, goblet and Paneth cells are not specified per se C_LIO_LINiche factors, especially BMP signaling, define goblet and Paneth phenotypes C_LI Enterocytes and four secretory cell types derive from stem cells located in intestinal crypts. Whereas secretory goblet and Paneth cells have long been considered distinct, we find high overlap in their transcripts and sites of accessible chromatin, in marked contrast to those of sibling enteroendocrine or tuft cells. Mouse and human goblet and Paneth cells express extraordinary fractions of selective antimicrobial genes, reflecting specific and variable gene responses to local niche signals. Wnt signaling retains few ATOH1+ secretory daughters in crypt bottoms, where an absence of BMP signaling potently induces Paneth features; those that move away from crypt bottoms acquire classic goblet properties. These post-mitotic cellular phenotypes and their underlying accessible cis-elements interconvert readily. Thus, goblet and Paneth properties represent alternative manifestations of a single versatile signal-responsive secretory cell. These findings reveal exquisite niche-dependent cell plasticity and the cis-regulatory dynamics of an updated unitarian model of the intestinal epithelial lineage.

cell biology↗

bioRxiv2024

A CXCR4 partial agonist improves immunotherapy by targeting polymorphonuclear myeloid-derived suppressor cells and cancer-driven granulopoiesis

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that potently impair immunotherapy responses. The chemokine receptor CXCR4, a central regulator of hematopoiesis, represents an attractive PMN-MDSC target1. Here, we fused a secreted CXCR4 partial agonist TFF2 to mouse serum albumin (MSA) and demonstrated that TFF2-MSA peptide synergized with anti-PD-1 to induce tumor regression or eradication, inhibited distant metastases, and prolonged survival in multiple gastric cancer (GC) models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track PMN-MDSC in vivo, we found TFF2-MSA selectively reduced the immunosuppressive Hdc-GFP+ CXCR4hi tumor PMN-MDSCs while preserving proinflammatory neutrophils, thereby boosting CD8+ T cell-mediated anti-tumor response together with anti-PD-1. Furthermore, TFF2-MSA systemically reduced PMN-MDSCs and bone marrow granulopoiesis. In contrast, CXCR4 antagonism plus anti-PD-1 failed to provide a similar therapeutic benefit. In GC patients, expanded PMN-MDSCs containing a prominent CXCR4+LOX-1+ subset are inversely correlated with the TFF2 level and CD8+ T cells in circulation. Collectively, our studies introduce a strategy of using CXCR4 partial agonism to restore anti-PD-1 sensitivity in GC by targeting PMN-MDSCs and granulopoiesis.

cancer biology↗

bioRxiv2024

Nociceptive neurons interact directly with gastric cancer cells via a CGRP/Ramp1 axis to promote tumor progression

Cancer cells have been shown to exploit neurons to modulate their survival and growth, including through establishment of neural circuits within the central nervous system (CNS) 1-3. Here, we report a distinct pattern of cancer-nerve interactions between the peripheral nervous system (PNS) and gastric cancer (GC). In multiple GC mouse models, nociceptive nerves demonstrated the greatest degree of nerve expansion in an NGF-dependent manner. Neural tracing identified CGRP+ peptidergic neurons as the primary gastric sensory neurons. Three-dimensional co-culture models showed that sensory neurons directly connect with gastric cancer spheroids through synapse-like structures. Chemogenetic activation of sensory neurons induced the release of calcium into the cytoplasm of cancer cells, promoting tumor growth and metastasis. Pharmacological ablation of sensory neurons or treatment with CGRP inhibitors suppressed tumor growth and extended survival. Depolarization of gastric tumor membranes through in vivo optogenetic activation led to enhanced calcium flux in nodose ganglia and CGRP release, defining a cancer cell-peptidergic neuronal circuit. Together, these findings establish the functional connectivity between cancer and sensory neurons, identifying this pathway as a potential therapeutic target.

cancer biology↗

bioRxiv2023

Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis.

Osteoarthritis (OA), which carries an enormous disease burden across the world, is characterised by irreversible degeneration of articular cartilage (AC), and subsequently bone. The cellular cause of OA is unknown. Here, using lineage tracing in mice, we show that the BMP-antagonist Gremlin 1 (Grem1) marks a novel chondrogenic progenitor (CP) cell population in the articular surface that generates joint cartilage and subchondral bone during development and adulthood. Notably, this CP population is depleted in injury-induced OA, and with age. OA is also induced by toxin-mediated ablation of Grem1 CP cells in young mice. Transcriptomic analysis and functional modelling in mice revealed articular surface Grem1-lineage cells are dependent on Foxo1; ablation of Foxo1 in Grem1-lineage cells led to early OA. This analysis identified FGFR3 signalling as a therapeutic target, and injection of its activator, FGF18, caused proliferation of Grem1-lineage CP cells, increased cartilage thickness, and reduced OA pathology. We propose that OA arises from the loss of CP cells at the articular surface secondary to an imbalance in progenitor cell homeostasis and present a new progenitor population as a locus for OA therapy.

cell biology↗