| 1. |
- Bozoky, Benedek, et al.
(author)
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Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium
- 2021
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In: Neoplasia. - : Elsevier. - 1522-8002 .- 1476-5586. ; 23:12, s. 1300-1306
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Journal article (peer-reviewed)abstract
- Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors. Based on transcriptomic classifiers, basal-like and classical PDAC subtypes have been defined that differ in prognosis. Cells of both subtypes can coexist in individual tumors; however, the contribution of either clonal heterogeneity or microenvironmental cues to subtype heterogeneity is unclear. Here, we report the spatial tumor phenotype dynamics in a cohort of patients in whom PDAC infiltrated the duodenal wall, and identify the duodenal epithelium as a distinct PDAC microniche. Materials and methods: We used serial multiplex quantitative immunohistochemistry (smq-IHC) for 24 proteins to phenotypically chart PDAC tumor cells in patients whose tumors infiltrated the duodenal epithelium. Additionally, we used a genetically engineered mouse model to study the PDAC cell phenotype in the small intestinal epithelium in a controlled genetic background. Result: We show that pancreatic cancer cells revert to non-destructive growth upon integration into the duodenal epithelium, where they adopt traits of intestinal cell differentiation, associated with phenotypical stabilization of the classical subtype. The integrated tumor cells replace epithelial cells in an adenoma-like manner, as opposed to invasive growth in the submucosa. Finally, we show that this phenomenon is shared between species, by confirming duodenal integration and phenotypic switching in a genetic PDAC mouse model. Discussion: Our results identify the duodenal epithelium as a distinct PDAC microniche and tightly link microenvironmental cue to cancer transcriptional subtypes. The phenomenon of "intestinal mimicry" provides a unique opportunity for the systematic investigation of microenvironmental influences on pancreatic cancer plasticity.
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| 2. |
- Krampert, Monika, et al.
(author)
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A gain-of-function mutation in the PDGFR-beta alters thekinetics of injury response in liver and skin
- 2008
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In: Laboratory Investigation. - : USCAP. - 0023-6837 .- 1530-0307. ; 88:11, s. 1204-1214
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Journal article (peer-reviewed)abstract
- Platelet-derived growth factor (PDGF) isoforms stimulate cell proliferation, migration and survival. We recently generated mice carrying a gain-of-function mutation within the activation loop of PDGF beta-receptor (PDGFR-beta D849N). Embryonic fibroblasts derived from these mice show elevated basal phosphorylation and altered kinetics for ligand-induced activation of PDGFR-beta, as well as enhanced proliferation and migration. To investigate the effect of this mutation in vivo, we used carbon tetrachloride-induced liver injury as a model system. We observed a higher basal activation of mutant PDGFR-beta in unchallenged livers; however, the difference in activation upon carbon tetrachloride stimulation was lower than expected, an effect that might be explained by a delayed response of the mutated receptor toward reactive oxygen species. Mutant mice showed enhanced proliferation of nonparenchymal liver cells and activation of hepatic stellate cells, leading to a small increase in early fibrosis formation. Another mouse strain lacking the binding site for phosphatidylinositol-3' kinase in PDGFR-beta showed the reverse phenotype. These results suggest an important role for PDGFR-beta signaling in the early injury-response. We confirmed this hypothesis with a second injury model, cutaneous wound healing, where we observed earlier proliferation and formation of granulation tissue in D849N-mutant mice.
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| 3. |
- Li, Ronggui, et al.
(author)
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Deletion of exon I of SMAD7 in mice results in altered B cell responses
- 2006
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In: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 176:11, s. 6777-6784
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Journal article (peer-reviewed)abstract
- The members of the TGF-beta superfamily, i.e., TGF-beta isoforms, activins, and bone morphogenetic proteins, regulate growth, differentiation, and apoptosis, both during embryonic development and during postnatal life. Smad7 is induced by the TGF-beta superfamily members and negatively modulates their signaling, thus acting in a negative, autocrine feedback manner. In addition, Smad7 is induced by other stimuli. Thus, it can fine-tune and integrate TGF-beta signaling with other signaling pathways. To investigate the functional role(s) of Smad7 in vivo, we generated mice deficient in exon I of Smad7, leading to a partial loss of Smad7 function. Mutant animals are viable, but significantly smaller on the outbred CD-1 mouse strain background. Mutant B cells showed an overactive TGF-beta signaling measured as increase of phosphorylated Smad2-positive B cells compared with B cells from wild-type mice. In agreement with this expected increase in TGF-beta signaling, several changes in B cell responses were observed. Mutant B cells exhibited increased Ig class switch recombination to IgA, significantly enhanced spontaneous apoptosis in B cells, and a markedly reduced proliferative response to LPS stimulation. Interestingly, LPS treatment reverted the apoptotic phenotype in the mutant cells. Taken together, the observed phenotype highlights a prominent role for Smad7 in development and in regulating the immune system's response to TGF-beta.
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| 4. |
- Magnusson, Peetra U., et al.
(author)
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Platelet-derived growth factor receptor-beta constitutive activity promotes angiogenesis in vivo and in vitro
- 2007
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 27:10, s. 2142-2149
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Journal article (peer-reviewed)abstract
- OBJECTIVE - Knockout studies have demonstrated crucial roles for the platelet-derived growth factor-B and its cognate receptor, platelet-derived growth factor receptor-β (PDGFR-β), in blood vessel maturation, that is, the coverage of newly formed vessels with mural cells/pericytes. This study describes the consequences of a constitutively activating mutation of the PDGFR-β (Pdgfrb) introduced into embryonic stem cells with respect to vasculogenesis/angiogenesis in vitro and in vivo. METHODS AND RESULTS - Embryonic stem cells were induced to either form teratomas in vivo or embryoid bodies, an in vitro model for mouse embryogenesis. Western blotting studies on embryoid bodies showed that expression of a single allele of the mutant Pdgfrb led to increased levels of PDGFR-β tyrosine phosphorylation and augmented downstream signal transduction. This was accompanied by enhanced vascular development, followed by exaggerated angiogenic sprouting with abundant pericyte coating as shown by immunohistochemistry/immunofluorescence. Pdgfrb embryoid bodies were characterized by increased expression of vascular endothelial growth factor (VEGF)-A and VEGF receptor-2; neutralizing antibodies against VEGF-A/VEGF receptor-2 blocked vasculogenesis and angiogenesis in mutant embryoid bodies. Moreover, Pdgfrb embryonic stem cell-derived teratomas in nude mice were more densely vascularized than wild-type teratomas. CONCLUSION - Increased PDGFR-β kinase activity is associated with elevated expression of VEGF-A and VEGF receptor-2, acting directly on endothelial cells and resulting in increased vessel formation.
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| 5. |
- Moro, Carlos Fernandez, et al.
(author)
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An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
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Journal article (peer-reviewed)abstract
- A perimetastatic capsule is a strong positive prognostic factor in liver metastases, but its origin remains unclear. Here, we systematically quantify the capsule's extent and cellular composition in 263 patients with colorectal cancer liver metastases to investigate its clinical significance and origin. We show that survival improves proportionally with increasing encapsulation and decreasing tumor-hepatocyte contact. Immunostaining reveals the gradual zonation of the capsule, transitioning from benign-like NGFR(high) stroma at the liver edge to FAP(high) stroma towards the tumor. Encapsulation correlates with decreased tumor viability and preoperative chemotherapy. In mice, chemotherapy and tumor cell ablation induce capsule formation. Our results suggest that encapsulation develops where tumor invasion into the liver plates stalls, representing a reparative process rather than tumor-induced desmoplasia. We propose a model of metastases growth, where the efficient tumor colonization of the liver parenchyma and a reparative liver injury reaction are opposing determinants of metastasis aggressiveness.
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