The Experts below are selected from a list of 1821 Experts worldwide ranked by ideXlab platform
Ginette Serrero - One of the best experts on this subject based on the ideXlab platform.
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the growth factor Granulin interacts with cyclin t1 and modulates p tefb dependent transcription
Molecular and Cellular Biology, 2002Co-Authors: Mainul Hoque, Michael B Mathews, Tsafi Peery, Tara M Young, Ginette SerreroAbstract:Cyclin T1, together with the kinase CDK9, is a component of the transcription elongation factor P-TEFb which binds the human immunodeficiency virus type 1 (HIV-1) transactivator Tat. P-TEFb facilitates transcription by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II. Cyclin T1 is an exceptionally large cyclin and is therefore a candidate for interactions with regulatory proteins. We identified Granulin as a cyclin T1-interacting protein that represses expression from the HIV-1 promoter in transfected cells. The Granulins, mitogenic growth factors containing repeats of a cysteine-rich motif, were reported previously to interact with Tat. We show that Granulin formed stable complexes in vivo and in vitro with cyclin T1 and Tat. Granulin bound to the histidine-rich domain of cyclin T1, which was recently found to bind to the CTD, but not to cyclin T2. Binding of Granulin to P-TEFb inhibited the phosphorylation of a CTD peptide. Granulin expression inhibited Tat transactivation, and tethering experiments showed that this effect was due, at least in part, to a direct action on cyclin T1 in the absence of Tat. In addition, Granulin was a substrate for CDK9 but not for the other transcription-related kinases CDK7 and CDK8. Thus, Granulin is a cellular protein that interacts with cyclin T1 to inhibit transcription.
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stimulation of pc cell derived growth factor epithelin Granulin precursor expression by estradiol in human breast cancer cells
Biochemical and Biophysical Research Communications, 1999Co-Authors: Runqing Lu, Ginette SerreroAbstract:PC cell-derived growth factor (PCDGF) is an 88 kDa glycosylated protein isolated from a highly tumorigenic mouse teratoma derived cell line which is similar to the epithelin/Granulin precursor. Using Northern blot and western blot analyses, we detect the expression of PCDGF mRNA and protein in MCF-7 human breast cancer cells. We show that 17-β-estradiol stimulates PCDGF mRNA and protein expression in a time and dose-dependent manner. The stimulation of PCDGF expression by 17-β-estradiol was observed as early as 4 hours and reached a maximum at 12 hours. Maximal stimulation of PCDGF mRNA and protein expression by 17-β-estradiol was observed at a concentration of 10−8M. The stimulation of PCDGF expression by 17-β-estradiol was completely inhibited by treatment with actinomycin D and with the antiestrogen 4-hydroxytamoxifen. The stimulation of PCDGF expression was also demonstrated in another human estrogen-responsive cell line T47D. The results presented here provide evidence of a novel estradiol responsive gene product in human breast cancer cell lines and give information about the hormonal control of epithelin/Granulin (PCDGF) expression in these cells.
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inhibition of tumorigenicity of the teratoma pc cell line by transfection with antisense cdna for pc cell derived growth factor pcdgf epithelin Granulin precursor
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Haidi Zhang, Ginette SerreroAbstract:The PC cell line is a highly tumorigenic, insulin-independent, teratoma-derived cell line isolated from the nontumorigenic, insulin-dependent 1246 cell line. Studies of the PC cell growth properties have led to the purification of an 88-kDa secreted glycoprotein called PC cell-derived growth factor (PCDGF), which has been shown to stimulate the growth of PC cells as well as 3T3 fibroblasts. Sequencing of PCDGF cDNA demonstrated its identity to the precursor of a family of 6-kDa double-cysteine-rich polypeptides called epithelins or Granulins (epithelin/Granulin precursor). Since PCDGF was isolated from highly tumorigenic cells, its level of expression was examined in PC cells as well as in nontumorigenic and moderately tumorigenic cells from which PC cells were derived. Northern blot and Western blot analyses indicate that the levels of PCDGF mRNA and protein were very low in the nontumorigenic cells and increased in tumorigenic cell lines in a positive correlation with their tumorigenic properties. Experiments were performed to determine whether the autocrine production of PCDGF was involved in the tumorigenicity of PC cells. For this purpose, we examined the in vivo growth properties in syngeneic C3H mice of PC cells where PCDGF expression had been inhibited by transfection of antisense PCDGF cDNA. The results show that inhibition of PCDGF expression resulted in a dramatic inhibition of tumorigenicity of the transfected cells when compared with empty-vector control cells. These data demonstrate the importance in tumor formation of overexpression of the novel growth factor PCDGF.
Bjorn Nilsson - One of the best experts on this subject based on the ideXlab platform.
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abstract c75 Granulin expressing bone marrow cells promote the outgrowth of indolent tumors
Cancer Research, 2009Co-Authors: Sandra S Mcallister, Christina Scheel, Bjorn Nilsson, Ann M Gifford, Ferenc Reinhardt, Mark Bray, Ann E Carpenter, Benjamin L EbertAbstract:We previously demonstrated that certain vigorously growing xenografted human carcinomas (“instigators”) stimulate the growth of otherwise‐indolent carcinoma cells and metastases (“responders”) implanted at distant anatomical sites — a process we termed “systemic instigation” (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once‐indolent cells was unknown. Here, we demonstrate that Sca1+/cKit− BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or the admixture of Sca1+/cKit− BMCs harvested from instigator‐bearing mice, form with a desmoplastic stroma. Stromal desmoplasia, the accumulation of a myofibroblast‐rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas. The Sca1+/cKit− BMCs do not directly give rise to stromal myofibroblasts; instead, we found that factors secreted by these BMCs induce fibroblasts to express alpha‐smooth muscle actin (ACTA2), a myofibroblast marker. Gene expression profiling of the Sca1+/cKit− BMCs from instigator‐ and non‐instigator‐bearing mice identified Granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found: i) that Granulin is indeed expressed by bone marrow‐derived cells that are recruited into the responding tumor stroma; ii) that treatment of human mammary fibroblasts with Granulin induces ACTA2 expression; iii) that Granulin treatment is sufficient to enhance responding tumor growth in vivo . Mining of existing microarray datasets revealed that high Granulin expression is correlated with the expression of ACTA2 in human breast cancers and is associated with shorter disease‐free survival of breast cancer patients. Our results indicate that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of Granulin‐expressing Sca1+/cKit− in the bone marrow. Citation Information: Cancer Res 2009;69(23 Suppl):C75.
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Abstract C75: Granulin‐expressing bone marrow cells promote the outgrowth of indolent tumors
Cancer Research, 2009Co-Authors: Sandra S Mcallister, Christina Scheel, Bjorn Nilsson, Ann M Gifford, Ferenc Reinhardt, Mark Bray, Ann E Carpenter, Benjamin L Ebert, Robert A. WeinbergAbstract:We previously demonstrated that certain vigorously growing xenografted human carcinomas (“instigators”) stimulate the growth of otherwise‐indolent carcinoma cells and metastases (“responders”) implanted at distant anatomical sites — a process we termed “systemic instigation” (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once‐indolent cells was unknown. Here, we demonstrate that Sca1+/cKit− BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or the admixture of Sca1+/cKit− BMCs harvested from instigator‐bearing mice, form with a desmoplastic stroma. Stromal desmoplasia, the accumulation of a myofibroblast‐rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas. The Sca1+/cKit− BMCs do not directly give rise to stromal myofibroblasts; instead, we found that factors secreted by these BMCs induce fibroblasts to express alpha‐smooth muscle actin (ACTA2), a myofibroblast marker. Gene expression profiling of the Sca1+/cKit− BMCs from instigator‐ and non‐instigator‐bearing mice identified Granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found: i) that Granulin is indeed expressed by bone marrow‐derived cells that are recruited into the responding tumor stroma; ii) that treatment of human mammary fibroblasts with Granulin induces ACTA2 expression; iii) that Granulin treatment is sufficient to enhance responding tumor growth in vivo . Mining of existing microarray datasets revealed that high Granulin expression is correlated with the expression of ACTA2 in human breast cancers and is associated with shorter disease‐free survival of breast cancer patients. Our results indicate that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of Granulin‐expressing Sca1+/cKit− in the bone marrow. Citation Information: Cancer Res 2009;69(23 Suppl):C75.
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abstract 5666 systemic instigation of stromal desmoplasia and indolent tumor outgrowth via activation of Granulin expressing sca1 ckit bone marrow cells
Cancer Research, 2009Co-Authors: Sandra S Mcallister, Bjorn Nilsson, Ann M Gifford, Ferenc Reinhardt, Benjamin L Ebert, Tan A Ince, Robert A. WeinbergAbstract:AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Stromal desmoplasia, the accumulation of a myofibroblast-rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas, yet the manner in which tumors acquire such a stroma is poorly understood. We previously demonstrated that certain vigorously growing xenografted human carcinomas (\#8220;instigators\#8221;) stimulate the growth of otherwise-indolent carcinoma cells, metastases, and segments of human tumor specimens (\#8220;responders\#8221;) implanted at distant anatomical sites - a process we termed \#8220;systemic instigation\#8221; (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once-indolent cells was unknown. Here, we demonstrate that Sca1+/cKit- BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or admixture of Sca1+/cKit- BMCs harvested from instigator-bearing mice, form with a desmoplastic stroma. The activated Sca1+/cKit- BMCs represent approximately two percent of the total bone marrow population and are unique in their tumor-promoting ability, as Sca1+/cKit- BMCs from non-instigator-bearing and control animals do not support responding tumor outgrowth. Furthermore, gene expression profiling of the Sca1+/cKit- BMCs from instigator- and non-instigator-bearing mice identified Granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found that Granulin is indeed expressed by bone marrow-derived cells that are recruited into the responding tumor stroma, and that Granulin treatment enhances the growth of responding tumors in vivo. Moreover, a series of in vitro studies revealed that Granulin does not directly affect the proliferation of the responder cells but, rather, induces fibroblasts to express alpha-smooth muscle actin (ACTA2), a myofibroblast marker. These myofibroblasts, in turn, enhance the growth of the responding tumor cells. Finally, by mining existing microarray datasets, we show that high Granulin expression in human breast cancers is associated with shorter disease-free survival. Our results reveal that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of Granulin-expressing Sca1+/cKit- in the bone marrow. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5666.
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Abstract #5666: Systemic instigation of stromal desmoplasia and indolent tumor outgrowth via activation of Granulin-expressing Sca1+/cKit- bone marrow cells
Cancer Research, 2009Co-Authors: Sandra S Mcallister, Bjorn Nilsson, Ann M Gifford, Ferenc Reinhardt, Benjamin L Ebert, Tan A Ince, Robert A. WeinbergAbstract:AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Stromal desmoplasia, the accumulation of a myofibroblast-rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas, yet the manner in which tumors acquire such a stroma is poorly understood. We previously demonstrated that certain vigorously growing xenografted human carcinomas (\#8220;instigators\#8221;) stimulate the growth of otherwise-indolent carcinoma cells, metastases, and segments of human tumor specimens (\#8220;responders\#8221;) implanted at distant anatomical sites - a process we termed \#8220;systemic instigation\#8221; (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once-indolent cells was unknown. Here, we demonstrate that Sca1+/cKit- BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or admixture of Sca1+/cKit- BMCs harvested from instigator-bearing mice, form with a desmoplastic stroma. The activated Sca1+/cKit- BMCs represent approximately two percent of the total bone marrow population and are unique in their tumor-promoting ability, as Sca1+/cKit- BMCs from non-instigator-bearing and control animals do not support responding tumor outgrowth. Furthermore, gene expression profiling of the Sca1+/cKit- BMCs from instigator- and non-instigator-bearing mice identified Granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found that Granulin is indeed expressed by bone marrow-derived cells that are recruited into the responding tumor stroma, and that Granulin treatment enhances the growth of responding tumors in vivo. Moreover, a series of in vitro studies revealed that Granulin does not directly affect the proliferation of the responder cells but, rather, induces fibroblasts to express alpha-smooth muscle actin (ACTA2), a myofibroblast marker. These myofibroblasts, in turn, enhance the growth of the responding tumor cells. Finally, by mining existing microarray datasets, we show that high Granulin expression in human breast cancers is associated with shorter disease-free survival. Our results reveal that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of Granulin-expressing Sca1+/cKit- in the bone marrow. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5666.
Andrew Bateman - One of the best experts on this subject based on the ideXlab platform.
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structure dissection of zebrafish proGranulins identifies a well folded Granulin epithelin module protein with pro cell survival activities
Protein Science, 2018Co-Authors: Feng Ni, Ping Xu, Andrew Bateman, H P J Bennett, Babykumari P Chitramuthu, Ping WangAbstract:: The ancient and pluripotent proGranulins contain multiple repeats of a cysteine-rich sequence motif of ∼60 amino acids, called the Granulin/epithelin module (GEM) with a prototypic structure of four β-hairpins zipped together by six inter-hairpin disulfide bonds. Prevalence of this disulfide-enforced structure is assessed here by an expression screening of 19 unique GEM sequences of the four proGranulins in the zebrafish genome, proGranulins 1, 2, A and B. While a majority of the expressed GEM peptides did not exhibit uniquely folded conformations, module AaE from proGranulin A and AbB from proGranulin B were found to fold into the protopypic 4-hairpin structure along with disulfide formation. Module AaE has the most-rigid three-dimensional structure with all four β-hairpins defined using high-resolution (H-15 N) NMR spectroscopy, including 492 inter-proton nuclear Overhauser effects, 23 3 J(HN,Hα ) coupling constants, 22 hydrogen bonds as well as 45 residual dipolar coupling constants. Three-dimensional structure of AaE and the partially folded AbB re-iterate the conformational stability of the N-terminal stack of two beta-hairpins and varying degrees of structural flexibility for the C-terminal half of the 4-hairpin global fold of the GEM repeat. A cell-based assay demonstrated a functional activity for the zebrafish Granulin AaE in promoting the survival of neuronal cells, similarly to what has been found for the corresponding Granulin E module in human proGranulin. Finally, this work highlights the remaining challenges in structure-activity studies of proteins containing the GEM repeats, due to the apparent prevalence of structural disorder in GEM motifs despite potentially a high density of intramolecular disulfide bonds.
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chromatographic methods for the purification of Granulin peptides
Methods of Molecular Biology, 2018Co-Authors: Andrew Bateman, H P J Bennett, Babykumari P ChitramuthuAbstract:: ProGranulin is composed of seven repeating cysteine-rich Granulin domains. In some cells and tissues, the proGranulin is fragmented by proteolysis to generate the Granulin modules as individual peptides, which are collectively referred to as Granulins. These peptides are often biologically active, but the activity need not be identical to that of the parental proGranulin from which they are derived. Thus, some Granulin peptides stimulate cell proliferation, as does proGranulin itself, while other Granulin peptides suppress proliferation. Similarly, some Granulin peptides promote inflammation even though proGranulin itself suppresses inflammation. Investigating the structural and biological properties of Granulin peptides is challenging. Here we discuss methods that employ reversed-phase high-performance liquid chromatography (RP-HPLC) and in some instances size-exclusion high-performance liquid chromatography (SE-HPLC) to isolate Granulin peptides from tissues, in particular those that are rich in inflammatory cells such as neutrophils, bone marrow, or hematopoietic organs of teleost fish.
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growing a tumor stroma a role for Granulin and the bone marrow
Journal of Clinical Investigation, 2011Co-Authors: Andrew BatemanAbstract:The tumor stroma is critical in cancer progression; understanding its formation is therefore important biologically and therapeutically. In this issue of the JCI, Elkabets et al. report on the generation of data in mice that lead them to propose that certain tumors can stimulate the growth of a second otherwise quiescent or indolent tumor in the same animal by stimulating stromal formation. Granulin-expressing Sca+Kit– hematopoietic progenitor cells in the bone marrow of the tumor host were required to mediate this effect. These data shed new light on the importance of the bone marrow in tumor growth and the role of Granulin in carcinogenesis.
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Granulins: the structure and function of an emerging family of growth factors
Journal of Endocrinology, 1998Co-Authors: Andrew Bateman, Hugh P. J. BennettAbstract:: The Granulin/epithelin motif defines a family of structurally unique proteins, of great evolutionary antiquity, which have been implicated as regulators of cell growth. Recurrent in Granulin research are the surprising parallels between the Granulin and EGF systems. Both are cysteinerich peptides of approximately 6 kDa that can modify cell growth. They show similar, but not identical, biological activities, although Granulin/epithelin peptides do not bind EGF receptors; the three-dimensional folds of Granulin and EGF are partially superimposible; and the precursors for mammalian Granulin/epithelins and EGF are both organized as multiple repeats of conserved cysteine modules. Given the dissimilarity between amino acid sequences of members of the Granulin/epithelin family and EGF-related peptides, the parallelism between the two systems probably represents convergent evolution towards related solutions to common biological problems. The Granulin/epithelin precursor gene is expressed throughout the body, but its expression is predominantly in epithelial and haematopoietic cells. There is a great deal of versatility in the means by which cells process and handle the Granulin/epithelin precursor. In some instances, the precursor is secreted intact (Zhou et al. 1993), and in others it is stored in a vesicular organelle, such as the sperm acrosome (Baba et al. 1993a). It may be processed into small 6-kDa peptides, which, in the neutrophil, can also be stored in vesicles (Bateman et al. 1990, Couto et al. 1992). The 6-kDa peptide forms, the intact precursor, and related proteins such as TGFe, regulate the growth of epithelial and mesenchymal cells. Epithelial cells express putative receptors for Granulin/epithelin peptides and TGFe (Culouscou et al. 1993, Parnell et al. 1995). Thus, although much remains to be clarified, Granulin/epithelin polypeptides and related proteins are emerging as widely distributed potential autocrine and paracrine growth modulating factors for epithelial and mesenchymal cells.
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Characterization of Granulins, a novel family of cysteine rich growth modulating peptides
1994Co-Authors: Vijay Bhandari, Andrew BatemanAbstract:Granulins (epithelins) are cysteine rich polypeptides with pleiotropic effects on epithelial cell growth in vitro. The human Granulin cDNA predicts a 593 amino acid glycoprotein precursor containing seven and one-half Granulin-like repeats arranged in tandem. The rat Granulin precursor cDNA predicts a 589 residue glycoprotein with an overall identity of 75% with human proGranulin. The single copy human Granulin gene is located on chromosome 17. The protein coding region of the Granulin gene spans 4 kilobases and contains 12 exons with each repeat encoded by two exons. The 5$ sp prime$ flanking region of the human Granulin gene lacks a TATA box but has several CCAAT boxes, and exhibits heterogeneity in transcription initiation sites. The Granulin precursor is processed differently depending on cell type, and secretion of the Granulin gene products is both constitutive and regulated. The Granulin gene is expressed in a variety of adult and fetal tissues derived from all three embryonic germ layers. In vitro, the Granulin gene is expressed in cell types of diverse lineages, including epithelial cells, lymphoid and myeloid cells, and fibroblasts, whereas its expression in situ is restricted to hematopoietic and some epithelial cells.
Dannielle D Engle - One of the best experts on this subject based on the ideXlab platform.
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macrophage derived Granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer
Cancer Research, 2018Co-Authors: Valeria Quaranta, Sebastian R Nielsen, Carolyn Rainer, Dannielle D Engle, Meirion Raymant, Muhammad S Ahmed, Arthur Taylor, Trish Murray, Fiona Campbell, Daniel H PalmerAbstract:The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immunoprotective role of the metastatic tumor microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived Granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Granulin expression by macrophages was induced in response to colony-stimulating factor-1. Genetic depletion of Granulin reduced the formation of a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumors are largely resistant to anti-PD-1 therapy, blockade of PD-1 in Granulin-depleted tumors restored the anti-tumor immune defense and dramatically decreased metastatic tumor burden. These findings suggest that targeting Granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumors, which are refractory to immune checkpoint inhibitors, into tumors that respond to immune checkpoint inhibition therapies.
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macrophage derived Granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer
bioRxiv, 2017Co-Authors: Valeria Quaranta, Sebastian R Nielsen, Carolyn Rainer, Dannielle D Engle, Meirion Raymant, Muhammad S Ahmed, Arthur Taylor, Trish Murray, Fiona Campbell, Daniel H PalmerAbstract:The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived Granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Mechanistically, we find that Granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of Granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in Granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting Granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.
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corrigendum macrophage secreted Granulin supports pancreatic cancer metastasis by inducing liver fibrosis
Nature Cell Biology, 2016Co-Authors: Sebastian R Nielsen, Valeria Quaranta, Andrea Linford, Perpetua Emeagi, Carolyn Rainer, Almudena Santos, Lucy Ireland, Takao Sakai, Keiko Sakai, Dannielle D EngleAbstract:Corrigendum: Macrophage-secreted Granulin supports pancreatic cancer metastasis by inducing liver fibrosis
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macrophage secreted Granulin supports pancreatic cancer metastasis by inducing liver fibrosis
Nature Cell Biology, 2016Co-Authors: Sebastian R Nielsen, Valeria Quaranta, Andrea Linford, Perpetua Emeagi, Carolyn Rainer, Almudena Santos, Lucy Ireland, Takao Sakai, Keiko Sakai, Dannielle D EngleAbstract:Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. Macrophages enhance metastasis in many cancer types; however, the role of macrophages in PDAC liver metastasis remains poorly understood. Here we found that PDAC liver metastasis critically depends on the early recruitment of Granulin-secreting inflammatory monocytes to the liver. Mechanistically, we demonstrate that Granulin secretion by metastasis-associated macrophages (MAMs) activates resident hepatic stellate cells (hStCs) into myofibroblasts that secrete periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment or genetic depletion of Granulin reduced hStC activation and liver metastasis. Interestingly, we found that circulating monocytes and hepatic MAMs in PDAC patients express high levels of Granulin. These findings suggest that recruitment of Granulin-expressing inflammatory monocytes plays a key role in PDAC metastasis and may serve as a potential therapeutic target for PDAC liver metastasis.
Sandra S Mcallister - One of the best experts on this subject based on the ideXlab platform.
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abstract c75 Granulin expressing bone marrow cells promote the outgrowth of indolent tumors
Cancer Research, 2009Co-Authors: Sandra S Mcallister, Christina Scheel, Bjorn Nilsson, Ann M Gifford, Ferenc Reinhardt, Mark Bray, Ann E Carpenter, Benjamin L EbertAbstract:We previously demonstrated that certain vigorously growing xenografted human carcinomas (“instigators”) stimulate the growth of otherwise‐indolent carcinoma cells and metastases (“responders”) implanted at distant anatomical sites — a process we termed “systemic instigation” (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once‐indolent cells was unknown. Here, we demonstrate that Sca1+/cKit− BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or the admixture of Sca1+/cKit− BMCs harvested from instigator‐bearing mice, form with a desmoplastic stroma. Stromal desmoplasia, the accumulation of a myofibroblast‐rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas. The Sca1+/cKit− BMCs do not directly give rise to stromal myofibroblasts; instead, we found that factors secreted by these BMCs induce fibroblasts to express alpha‐smooth muscle actin (ACTA2), a myofibroblast marker. Gene expression profiling of the Sca1+/cKit− BMCs from instigator‐ and non‐instigator‐bearing mice identified Granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found: i) that Granulin is indeed expressed by bone marrow‐derived cells that are recruited into the responding tumor stroma; ii) that treatment of human mammary fibroblasts with Granulin induces ACTA2 expression; iii) that Granulin treatment is sufficient to enhance responding tumor growth in vivo . Mining of existing microarray datasets revealed that high Granulin expression is correlated with the expression of ACTA2 in human breast cancers and is associated with shorter disease‐free survival of breast cancer patients. Our results indicate that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of Granulin‐expressing Sca1+/cKit− in the bone marrow. Citation Information: Cancer Res 2009;69(23 Suppl):C75.
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Abstract C75: Granulin‐expressing bone marrow cells promote the outgrowth of indolent tumors
Cancer Research, 2009Co-Authors: Sandra S Mcallister, Christina Scheel, Bjorn Nilsson, Ann M Gifford, Ferenc Reinhardt, Mark Bray, Ann E Carpenter, Benjamin L Ebert, Robert A. WeinbergAbstract:We previously demonstrated that certain vigorously growing xenografted human carcinomas (“instigators”) stimulate the growth of otherwise‐indolent carcinoma cells and metastases (“responders”) implanted at distant anatomical sites — a process we termed “systemic instigation” (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once‐indolent cells was unknown. Here, we demonstrate that Sca1+/cKit− BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or the admixture of Sca1+/cKit− BMCs harvested from instigator‐bearing mice, form with a desmoplastic stroma. Stromal desmoplasia, the accumulation of a myofibroblast‐rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas. The Sca1+/cKit− BMCs do not directly give rise to stromal myofibroblasts; instead, we found that factors secreted by these BMCs induce fibroblasts to express alpha‐smooth muscle actin (ACTA2), a myofibroblast marker. Gene expression profiling of the Sca1+/cKit− BMCs from instigator‐ and non‐instigator‐bearing mice identified Granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found: i) that Granulin is indeed expressed by bone marrow‐derived cells that are recruited into the responding tumor stroma; ii) that treatment of human mammary fibroblasts with Granulin induces ACTA2 expression; iii) that Granulin treatment is sufficient to enhance responding tumor growth in vivo . Mining of existing microarray datasets revealed that high Granulin expression is correlated with the expression of ACTA2 in human breast cancers and is associated with shorter disease‐free survival of breast cancer patients. Our results indicate that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of Granulin‐expressing Sca1+/cKit− in the bone marrow. Citation Information: Cancer Res 2009;69(23 Suppl):C75.
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abstract 5666 systemic instigation of stromal desmoplasia and indolent tumor outgrowth via activation of Granulin expressing sca1 ckit bone marrow cells
Cancer Research, 2009Co-Authors: Sandra S Mcallister, Bjorn Nilsson, Ann M Gifford, Ferenc Reinhardt, Benjamin L Ebert, Tan A Ince, Robert A. WeinbergAbstract:AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Stromal desmoplasia, the accumulation of a myofibroblast-rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas, yet the manner in which tumors acquire such a stroma is poorly understood. We previously demonstrated that certain vigorously growing xenografted human carcinomas (\#8220;instigators\#8221;) stimulate the growth of otherwise-indolent carcinoma cells, metastases, and segments of human tumor specimens (\#8220;responders\#8221;) implanted at distant anatomical sites - a process we termed \#8220;systemic instigation\#8221; (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once-indolent cells was unknown. Here, we demonstrate that Sca1+/cKit- BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or admixture of Sca1+/cKit- BMCs harvested from instigator-bearing mice, form with a desmoplastic stroma. The activated Sca1+/cKit- BMCs represent approximately two percent of the total bone marrow population and are unique in their tumor-promoting ability, as Sca1+/cKit- BMCs from non-instigator-bearing and control animals do not support responding tumor outgrowth. Furthermore, gene expression profiling of the Sca1+/cKit- BMCs from instigator- and non-instigator-bearing mice identified Granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found that Granulin is indeed expressed by bone marrow-derived cells that are recruited into the responding tumor stroma, and that Granulin treatment enhances the growth of responding tumors in vivo. Moreover, a series of in vitro studies revealed that Granulin does not directly affect the proliferation of the responder cells but, rather, induces fibroblasts to express alpha-smooth muscle actin (ACTA2), a myofibroblast marker. These myofibroblasts, in turn, enhance the growth of the responding tumor cells. Finally, by mining existing microarray datasets, we show that high Granulin expression in human breast cancers is associated with shorter disease-free survival. Our results reveal that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of Granulin-expressing Sca1+/cKit- in the bone marrow. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5666.
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Abstract #5666: Systemic instigation of stromal desmoplasia and indolent tumor outgrowth via activation of Granulin-expressing Sca1+/cKit- bone marrow cells
Cancer Research, 2009Co-Authors: Sandra S Mcallister, Bjorn Nilsson, Ann M Gifford, Ferenc Reinhardt, Benjamin L Ebert, Tan A Ince, Robert A. WeinbergAbstract:AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Stromal desmoplasia, the accumulation of a myofibroblast-rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas, yet the manner in which tumors acquire such a stroma is poorly understood. We previously demonstrated that certain vigorously growing xenografted human carcinomas (\#8220;instigators\#8221;) stimulate the growth of otherwise-indolent carcinoma cells, metastases, and segments of human tumor specimens (\#8220;responders\#8221;) implanted at distant anatomical sites - a process we termed \#8220;systemic instigation\#8221; (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once-indolent cells was unknown. Here, we demonstrate that Sca1+/cKit- BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or admixture of Sca1+/cKit- BMCs harvested from instigator-bearing mice, form with a desmoplastic stroma. The activated Sca1+/cKit- BMCs represent approximately two percent of the total bone marrow population and are unique in their tumor-promoting ability, as Sca1+/cKit- BMCs from non-instigator-bearing and control animals do not support responding tumor outgrowth. Furthermore, gene expression profiling of the Sca1+/cKit- BMCs from instigator- and non-instigator-bearing mice identified Granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found that Granulin is indeed expressed by bone marrow-derived cells that are recruited into the responding tumor stroma, and that Granulin treatment enhances the growth of responding tumors in vivo. Moreover, a series of in vitro studies revealed that Granulin does not directly affect the proliferation of the responder cells but, rather, induces fibroblasts to express alpha-smooth muscle actin (ACTA2), a myofibroblast marker. These myofibroblasts, in turn, enhance the growth of the responding tumor cells. Finally, by mining existing microarray datasets, we show that high Granulin expression in human breast cancers is associated with shorter disease-free survival. Our results reveal that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of Granulin-expressing Sca1+/cKit- in the bone marrow. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5666.
