Nuclear translocation of <scp>FGFR</scp>1 and <scp>FGF</scp>2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

Coleman, Stacey J.; Chioni, Athina‐Myrto; Ghallab, Mohammed; Anderson, Rosaleen J.; Lemoine, Nick R.; Kocher, Hemant M.; Grose, Richard

doi:10.1002/emmm.201302698

Cited by 132 publications

(118 citation statements)

References 52 publications

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“…Overexpression of nFGFR1 is a feature of pancreatic ductal adenocarcinomas (PDACs). Nuclear FGFR1 and FGF‐2 are found in activated pancreatic stellate cells (PSCs), the cells primarily responsible for desmoplasia in pancreatic carcinomas (Coleman et al, 2014). Nuclear translocation of FGFR1 is necessary for the invasion of PSCs into regions containing pancreatic carcinomas, and subsequently, the formation of desmoplasia around the cancer cells.…”

Section: Role Of Nfgfr1 In Diseasementioning

confidence: 99%

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

Stachowiak

2016

Journal Cellular Physiology

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Genetic experiments have positioned the fgfr1 gene at the top of the gene hierarchy that governs gastrulation, as well as the subsequent development of the major body axes, nervous system, muscles, and bones, by affecting downstream genes that control the cell cycle, pluripotency, and differentiation, as well as microRNAs. Studies show that this regulation is executed by a single protein, the nuclear isoform of FGFR1 (nFGFR1), which integrates signals from development‐initiating factors, such as retinoic acid (RA), and operates at the interface of genomic and epigenomic information. nFGFR1 cooperates with a multitude of transcriptional factors (TFs), and targets thousands of genes encoding for mRNAs, as well as miRNAs in top ontogenic networks. nFGFR1 binds to the promoters of ancient proto‐oncogenes and tumor suppressor genes, in addition to binding to metazoan morphogens that delineate body axes, and construct the nervous system, as well as mesodermal and endodermal tissues. The discovery of pan‐ontogenic gene programming by integrative nuclear FGFR1 signaling (INFS) impacts our understanding of ontogeny, as well as developmental pathologies, and holds new promise for reconstructive medicine, and cancer therapy. J. Cell. Physiol. 231: 1199–1218, 2016. © 2016 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.

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Section: Role Of Nfgfr1 In Diseasementioning

confidence: 99%

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

Stachowiak

2016

Journal Cellular Physiology

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“…Organotypic 3D coculture models The development of the 3-dimensional (3D) coculture models (organotypic cultures) for pancreatic adenocarcinoma cells and stromal cells has been previously described in detail elsewhere (27)(28)(29). Briefly, collagen type I was mixed with Matrigel at different ratios, typically 3:1, in Transwells (Corning; SigmaAldrich) and placed in 24-well plates.…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

The Novel Oncolytic Adenoviral Mutant Ad5-3Δ-A20T Retargeted to αvβ6 Integrins Efficiently Eliminates Pancreatic Cancer Cells

Man

Davies

Coughlan

et al. 2018

Molecular Cancer Therapeutics

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Metastatic pancreatic ductal adenocarcinomas (PDAC) are incurable due to the rapid development of resistance to all current therapeutics. Oncolytic adenoviral mutants have emerged as a promising new strategy that negates such resistance. In contrast to normal tissue, the majority of PDACs express the avb6 integrin receptor. To exploit this feature, we modified our previously reported oncolytic adenovirus, AdDD, to selectively target avb6 integrins to facilitate systemic delivery. Structural modifications to AdDD include the expression of the small but potent avb6-binding peptide, A20FMDV2, and ablation of binding to the native coxsackie and adenovirus receptor (CAR) within the fiber knob region. The resultant mutant, Ad5-3D-A20T, infected and killed avb6 integrin-expressing cells more effectively than the parental wild-type (Ad5wt) virus and AdDD. Viral uptake through avb6 integrins rather than native viral receptors (CAR, avb3 and avb5 integrins) promoted viral propagation and spread. Superior efficacy of Ad5-3D-A20T compared with Ad5wt was demonstrated in 3D organotypic cocultures, and similar potency between the two viruses was observed in Suit-2 in vivo models. Importantly, Ad5-3D-A20T infected pancreatic stellate cells at low levels, which may further facilitate viral spread and cancer cell elimination either as a single agent or in combination with the chemotherapy drug, gemcitabine. We demonstrate that Ad5-3D-A20T is highly selective for avb6 integrin-expressing pancreatic cancer cells, and with further development, this new and exciting strategy can potentially be extended to improve the systemic delivery of adenoviruses to pancreatic cancer patients. Mol Cancer Ther; 17(2); 575-87. Ó2018 AACR.

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“…receptor and non-receptor mediated re-uptake into cells [13]; interaction with FGFRs within endosomes [14]; and translocation into the nucleus/ nucleolus [15]. In some FGFs, this functional diversity is achieved via the generation and differential targeting of low versus high molecular weight (HMW) isoforms.…”

Section: Biochemical Journalmentioning

confidence: 99%

Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function

Mikolajczak

Goodman

Hajihosseini

2016

Biochemical Journal

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Heterozygous mutations in the gene encoding fibroblast growth factor 10 (FGF10) or its cognate receptor, FGF-receptor 2 IIIb (FGFR2-IIIb) result in two human syndromes -LADD (lacrimo-auriculo-dento-digital) and ALSG (Aplasia of lacrimal and salivary glands). To date, the partial loss-of-FGF10 function in these patients has been attributed solely to perturbed paracrine signalling functions between FGF10-producing mesenchymal cells and FGF10-responsive epithelial cells. However, the functioning of a LADD-causing G138E FGF10 mutation, which falls outside its receptor interaction interface, has remained enigmatic. In this study, we interrogated this mutation in the context of FGF10's protein sequence and threedimensional structure, and followed the subcellular fate of tagged proteins containing this or other combinatorial FGF10 mutations, in vitro. We report that FGF10 harbours two putative nuclear localization sequences, termed NLS1 and NLS2, which individually or co-operatively promote nuclear translocation of FGF10. Furthermore, FGF10 localizes to a subset of dense fibrillar components of the nucleolus. G138E falls within NLS1 and abrogates FGF10's nuclear translocation whilst attenuating its progression along the secretory pathway. Our findings suggest that in addition to its paracrine roles, FGF10 may normally play intracrine role/s within FGF10-producing cells. Thus, G138E may disrupt both paracrine and intracrine function/s of FGF10 through attenuated secretion and nuclear translocation, respectively. ABSTRACTHeterozygous mutations in the gene encoding fibroblast growth factor 10 (FGF10) or its cognate receptor, FGF-receptor 2 IIIb (FGFR2-IIIb) result in two human syndromes -LADD (lacrimo-auriculo-dento-digital) and ALSG (Aplasia of lacrimal and salivary glands). To date, the partial loss-of-FGF10 function in these patients has been attributed solely to perturbed paracrine signalling functions between FGF10-producing mesenchymal cells and FGF10-responsive epithelial cells.However, the functioning of a LADD-causing G138E FGF10 mutation, which falls outside its receptor interaction interface, has remained enigmatic. In this study, we interrogated this mutation in the context of FGF10's protein sequence and threedimensional structure, and followed the subcellular fate of tagged proteins containing this or other combinatorial FGF10 mutations, in vitro. We report that FGF10 harbours two putative nuclear localization sequences, termed NLS1 and NLS2, which individually or co-operatively promote nuclear translocation of FGF10. Furthermore, FGF10 localizes to a subset of dense fibrillar components of the nucleolus. G138E falls within NLS1 and abrogates FGF10's nuclear translocation whilst attenuating its progression along the secretory pathway. Our findings suggest that in addition to its paracrine roles, FGF10 may normally play intracrine role/s within FGF10-producing cells. Thus, G138E may disrupt both paracrine and intracrine function/s of FGF10 through attenuated secretion and nuclear translocation, respectively....

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Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

Cited by 132 publications

References 52 publications

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

The Novel Oncolytic Adenoviral Mutant Ad5-3Δ-A20T Retargeted to αvβ6 Integrins Efficiently Eliminates Pancreatic Cancer Cells

Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function

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