The Transcription Factor GLI1 Modulates the Inflammatory Response during Pancreatic Tissue Remodeling

Mathew, Esha; Collins, Meredith A.; Fernández‐Barrena, Maite G.; Holtz, Alexander M.; Yan, Wei; Hogan, James O.; Tata, Zachary; Allen, Benjamin L.; Fernández-Zapico, Martín E.; Magliano, Marina Pasca di

doi:10.1074/jbc.m114.556563

Cited by 44 publications

(43 citation statements)

References 54 publications

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“…SHH (and probably also IHH) induces desmoplastic stroma containing α‐smooth muscle actin (SMA)‐positive myofibroblasts and cancer‐associated fibroblasts (CAFs) around tumor cells. SHH from PDAC cells stimulates CAFs to induce GLI1 expression through the Hh‐PTCH1‐SMO cascade, leading to the expression in CAFs of GLI1 target genes such as interleukin (IL)‐6 and IL‐8 . Such cytokines and transforming growth factor‐β (TGFβ) from CAFs in turn stimulate PDAC cells to induce the expression of GLI2 and then GLI1 (Fig.…”

Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 99%

“…Furthermore, the chemokine receptor CXCR4, which is responsible for CXCL12‐mediated organ‐specific metastasis, is also up‐regulated by GLI1 and GLI2 in PDAC cells . In addition, experiments using other types of cells have demonstrated that GLI1 directly up‐regulates the expression of many other genes, such as telomerase reverse transcriptase ( TERT ), NANOG for immortality and stemness; interleukin ( IL )‐ 6 / 8 , colony stimulating factor 1 ( CSF1 / MCSF ) and C‐C motif chemokine ligand 2 ( CCL2 / MCP1 ) for inflammation (particularly in fibroblastic stroma cells); cysteine rich angiogenic inducer 61 ( CYR61 / CCN1 ) for angiogenesis; and the ATP‐binding cassette transporter gene ABCG2 for multi‐drug resistance. These results support the notion that GLI1 governs the hallmarks of the malignant nature of PDAC through target gene regulation.…”

Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 99%

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GLI1, a master regulator of the hallmark of pancreatic cancer

Kasai

2016

Pathology International

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Hedgehog signaling is highly conserved across species and governs proper embryonic development. Germline gene mutations that reduce this signaling activity cause a variety of developmental abnormalities such as holoprosencephaly, while those that enhance Hedgehog signaling activity induce a tumor-predisposition condition Nevoid basal cell carcinoma syndrome. Furthermore, dysregulated activation of Hedgehog signaling has been recognized in various sporadic malignancies, including pancreatic adenocarcinoma. Pancreatic adenocarcinoma develops through a multistep carcinogenesis starting with oncogenic mutation of the KRAS gene. During this process, precancerous or cancer cells secrete Hedgehog ligand proteins to promote characteristic desmoplastic stroma around the cells, which in turn activates the expression of the downstream transcription factor GLI1 inside the cells. The quantitative and spatiotemporal dysregulation of GLI1 subsequently leads to the expression of transcriptional target genes of GLI1 that govern the hallmark of malignant properties. Here, after a brief introductory outline, a perspective is offered of Hedgehog signaling with a special focus on the role of GLI1 in pancreatic carcinogenesis.

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Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 99%

Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 99%

GLI1, a master regulator of the hallmark of pancreatic cancer

Kasai

2016

Pathology International

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“…CAFs are phenotypically and functionally distinguishable from their normal counterparts in their differential expression and secretion of extracellular matrix (ECM) components and growth factors [3]. Several studies have demonstrated that normal fibroblasts have a role in maintaining epithelial homeostasis by suppressing proliferation and oncogenic potential of adjacent epithelia [4, 5]. However, following neoplastic transformation of epithelia, CAFs have been shown to promote tumor growth by inducing angiogenesis, inflammation, recruiting bone marrow–derived immunosuppressive cells, and remodeling the ECM [6, 7].…”

Section: Introductionmentioning

confidence: 99%

Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts

et al. 2016

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Pancreatic ductal adenocarcinoma (PDA) shows a rich stroma where cancer-associated fibroblasts (CAFs) represent the major cell type. CAFs are master secretors of proteins with pro-tumor features. CAF targeting remains a promising challenge for PDA, a devastating disease where treatments focusing on cancer cells have failed. We previously introduced a novel pharmacological CAF-targeting approach using the somatostatin analog SOM230 (pasireotide) that inhibits protein synthesis in CAFs, and subsequent chemoprotective features of CAF secretome. Using primary cultures of CAF isolated from human PDA resections, we here report that CAF secretome stimulates in vitro cancer cell survival, migration and invasive features, that are abolished when CAFs are treated with SOM230. Mechanistically, SOM230 inhibitory effect on CAFs depends on the somatostatin receptor subtype sst1 expressed in CAFs but not in non-activated pancreatic fibroblasts, and on protein synthesis shutdown through eiF4E-Binding Protein-1 (4E-BP1) expression decrease. We identify interleukin-6 as a SOM230-inhibited CAF-secreted effector, which stimulates cancer cell features through phosphoinositide 3-kinase activation. In vivo, mice orthotopically co-xenografted with the human pancreatic cancer MiaPaCa-2 cells and CAFs develop pancreatic tumors, on which SOM230 treatment does not inhibit growth but abrogates metastasis. Consistently, CAF secretome stimulates epithelial-to-mesenchymal transition in cancer cells, which is reversed upon CAF treatment with SOM230. Our results highlight a novel promising anti-metastatic potential for SOM230 indirectly targeting pancreatic cancer cell invasion through pharmacological inhibition of stromal CAFs.

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“…These studies also determined that canonical HH signaling was required for pancreatic recovery. Thus both GLI1 and HH are critical for regulation of the pancreatic microenvironment (Mathew et al, 2014).…”

Section: Involvement Of the Hh Pathway In Pancreatic Cancermentioning

confidence: 99%