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Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer [scRNA-seq]

ABSTRACT: A better understanding of the roles of signaling pathways differentially activated in distinct fibroblast populations will shed light on the complexity of fibroblast heterogeneity in pancreatic cancer. Here, we show that Hedgehog pathway inhibition alters the fibroblast composition towards a more inflammatory microenvironment, opening the possibility for future combination therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE156438 | GEO | 2021/02/01

REPOSITORIES: GEO

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Project description:Sivakumar2011 - Hedgehog Signaling Pathway This is the current model for the Hedgehog signaling pathway. The best data for mechanism of signaling has been worked out in Drosophila, so this model is based largely on Drosophila data. Hedgehog target genes vary from tissue to tissue, so the identities of individual target genes have not been listed. The main difference between the Drosophila and mammalian Hedgehog signaling pathways is the fact that there are three mammalian homologs of Cubitus interruptus, Gli1 Gli2 and Gli3. Some or all of the mammalian homologs may be proteolytically processed, but the data are controversial. There are two mammalian Ptc genes and three mammalian Hedgehog genes as well. The pathway for Sonic Hedgehog appears to be most similar to the Drosophila hedgehog pathway. References: Hedgehog signaling in animal development: paradigms and principles. Sonic hedgehog in the nervous system: functions, modifications and mechanisms. Hedgehog signal transduction: recent findings. Hedgehog signaling: Costal-2 bridges the transduction gap. This model is described in the article: A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways. Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S. Omics: a Journal of Integrative Biology. 2011; 15(10):729-737 Abstract: The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs. This model is hosted on BioModels Database and identified by: BIOMD0000000395. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer [scRNA-seq]

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