Huibin Yang

UNLABELLED: Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense stroma consisting of a prevalence of activated fibroblasts whose functional contributions to pancreatic tumorigenesis remain incompletely understood. In this study, we provide the first identification and characterization of mesenchymal stem cells (MSC) within the human PDA microenvironment, highlighting the heterogeneity of the fibroblast population. Primary patient PDA samples and low-passage human pancreatic cancer-associated fibroblast cultures were found to contain a unique population of cancer-associated MSCs (CA-MSC). CA-MSCs markedly enhanced the growth, invasion, and metastatic potential of PDA cancer cells. CA-MSCs secreted the cytokine GM-CSF that was required for tumor cell proliferation, invasion, and transendothelial migration. Depletion of GM-CSF in CA-MSCs inhibited the ability of these cells to promote tumor cell growth and metastasis. Together, these data identify a population of MSCs within the tumor microenvironment that possesses a unique ability, through GM-CSF signaling, to promote PDA survival and metastasis. SIGNIFICANCE: The role of stroma in pancreatic cancer is controversial. Here, we provide the first characterization of MSCs within the human PDA microenvironment and demonstrate that CA-MSCs promote tumorigenesis through the production of GM-CSF. These data identify a novel cytokine pathway that mediates mesenchymal-epithelial cross-talk and is amenable to therapeutic intervention. Cancer Discov; 6(8); 886-99. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.

Amyotrophic lateral sclerosis (ALS) is caused by a progressive degeneration of motor neurons. The cause of sporadic ALS is not known, but 1-2% of all cases are familial and caused by mutations in the copper-zinc superoxide dismutase (SOD1) gene. Transgenic SOD1 mice serve as a transgenic mouse model for these cases. Glial cell-derived neurotrophic factor (GDNF) has a potent trophic effect on motor neurons. Clinical trials in which growth factors have been systemically administered to ALS patients have not been effective, owing in part to the short half-life of these factors and their low concentrations at target sites. Gene transfer of therapeutic factors to motor neurons and/or their target cells, such as muscle, may overcome these problems. Previously, we and others have shown that intramuscularly administered adenovirus vector (AVR) results in foreign gene expression not only in muscle cells, but also in relevant motor neurons in the spinal cord, because of retrograde axonal transport. In this study we utilized an AVR to introduce GDNF into muscles of neonatal SOD1 mice. We showed that AVR-mediated GDNF expression delayed the onset of disease by 7 +/- 8 days (mean +/- SD), prolonged survival by 17 +/- 10 days, and delayed the decline in motor functions (as determined on a rotating rod) by 7-14 days. These results demonstrate that gene delivery to muscle and motor neurons has the potential to treat devastating neurodegenerative diseases such as ALS.

Among the recognition molecules that determine a neuron's interaction with other cells, L1 and CD24 have been suggested to cooperate with each other in neurite outgrowth and signal transduction. Here we report that binding of CD24 to L1 depends on α2,3-sialic acid on CD24, which determines the CD24 induced and cell type-specific promotion or inhibition of neurite outgrowth. Using knockout mutants, we could show that the CD24-induced effects on neurite outgrowth are mediated via L1, and not GPI-linked CD24, by trans-interaction of L1 with sialylated CD24. This glycoform is excluded together with L1 from raft microdomains, suggesting that molecular compartmentation in the surface membrane could play a role in signal transduction. Among the recognition molecules that determine a neuron's interaction with other cells, L1 and CD24 have been suggested to cooperate with each other in neurite outgrowth and signal transduction. Here we report that binding of CD24 to L1 depends on α2,3-sialic acid on CD24, which determines the CD24 induced and cell type-specific promotion or inhibition of neurite outgrowth. Using knockout mutants, we could show that the CD24-induced effects on neurite outgrowth are mediated via L1, and not GPI-linked CD24, by trans-interaction of L1 with sialylated CD24. This glycoform is excluded together with L1 from raft microdomains, suggesting that molecular compartmentation in the surface membrane could play a role in signal transduction. 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid Tris-buffered saline high pressure liquid chromatography phosphate-buffered saline poly-l-lysine Path-finding of growth cones and neurite outgrowth toward targets are important events in the developing and regenerating nervous system and in synaptic remodeling during learning and memory. Axonal guidance depends on molecules at the cell surface and in the extracellular matrix. The different and often changing combinations of molecularly associated recognition molecules at the cell surface are important determinants of the ways by which the cell surface communicates with the cell interior, where cell surface signals are integrated to influence cell behavior.Two recognition molecules, L1 of the immunoglobulin superfamily and CD24, a highly glycosylated mucin type glycoprotein, interact with each other functionally (1Kadmon G. von Bohlen und Halbach F. Horstkorte R. Eckert M. Altevogt P. Schachner M. Eur. J. Neurosci. 1995; 7: 993-1004Crossref PubMed Scopus (56) Google Scholar, 2Sammar M. Aigner S. Altevogt P. Biochim. Biophys. Acta. 1997; 1337: 287-294Crossref PubMed Scopus (45) Google Scholar). L1 is a 200-kDa homophilic and heterophilic adhesion molecule expressed by many postmitotic neurons in the central nervous system (for reviews, see Refs. 3Brümmendorf T. Kenwrick S. Rathjen F.G. Curr. Opin. Neurobiol. 1998; 8: 87-97Crossref PubMed Scopus (212) Google Scholar and 4Kamiguchi H. Hlavin M.L. Lemmon V. Mol. Cell. Neurosci. 1998; 12: 48-55Crossref PubMed Scopus (116) Google Scholar). It is one of the most potent promoters of neurite outgrowth in vitro known so far. Mutants of L1 in mice and men strongly underscore its importance during embryonic development in vivo (3Brümmendorf T. Kenwrick S. Rathjen F.G. Curr. Opin. Neurobiol. 1998; 8: 87-97Crossref PubMed Scopus (212) Google Scholar, 5Dahme M. Bartsch U. Martini R. Anliker B. Schachner M. Mantei N. Nat. Genet. 1997; 17: 346-349Crossref PubMed Scopus (410) Google Scholar, 6Cohen N.R. Taylor J.S. Scott L.B. Guillery R.W. Soriano P. Furley A.J. Curr. Biol. 1998; 8: 26-33Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar).CD24 is linked to the surface membrane by a glycosyl phosphatidylinositol anchor and is, therefore, unable to directly interact with cytoplasmic proteins. It is also known as heat-stable antigen or nectadrin with a peptide core of only 30 amino acids (for references, see Ref. 1Kadmon G. von Bohlen und Halbach F. Horstkorte R. Eckert M. Altevogt P. Schachner M. Eur. J. Neurosci. 1995; 7: 993-1004Crossref PubMed Scopus (56) Google Scholar). Similar to L1, it is highly expressed by neurons (7Nédelec J. Pierres M. Moreau H. Barbet J. Naquet P. Faivre-Sarrailh C. Rougon G. Eur. J. Biochem. 1992; 203: 433-440Crossref PubMed Scopus (35) Google Scholar, 8Shewan D. Calaora V. Nielsen P. Cohen J. Rougon G. Moreau H. J. Neurosci. 1996; 16: 2624-2634Crossref PubMed Google Scholar). The apparent molecular weight of CD24 varies considerably among cell types and also within each cell type, depending on its developmental stage due to differences in glycosylation pattern (for references, see Refs. 1Kadmon G. von Bohlen und Halbach F. Horstkorte R. Eckert M. Altevogt P. Schachner M. Eur. J. Neurosci. 1995; 7: 993-1004Crossref PubMed Scopus (56) Google Scholar and 7Nédelec J. Pierres M. Moreau H. Barbet J. Naquet P. Faivre-Sarrailh C. Rougon G. Eur. J. Biochem. 1992; 203: 433-440Crossref PubMed Scopus (35) Google Scholar). These observations suggest that post-translational modifications of CD24 play an important functional role. CD24 acts as a co-stimulator for various physiological functions. In the nervous system, CD24 has been reported to interact with L1 to stimulate cell adhesion and to increase intracellular Ca2+levels (1Kadmon G. von Bohlen und Halbach F. Horstkorte R. Eckert M. Altevogt P. Schachner M. Eur. J. Neurosci. 1995; 7: 993-1004Crossref PubMed Scopus (56) Google Scholar, 2Sammar M. Aigner S. Altevogt P. Biochim. Biophys. Acta. 1997; 1337: 287-294Crossref PubMed Scopus (45) Google Scholar). Interestingly, CD24 has been shown to inhibit neurite outgrowth of neonatal retinal ganglion cells and dorsal root ganglion neurons in culture (8Shewan D. Calaora V. Nielsen P. Cohen J. Rougon G. Moreau H. J. Neurosci. 1996; 16: 2624-2634Crossref PubMed Google by signal on observations on the functional and molecular L1 and CD24, we to functional Here we report that L1 is a for CD24 and that CD24 neurite outgrowth of dorsal root ganglion neurons and neurite outgrowth of neurons via interaction in with L1 at the cell surface of the neurite to underscore important observations in cell the of as of recognition molecules in the of L1 as a and of the M. S. S. N. J. R. Schachner M. 1998; 8: in the type of the L1 the of L1 as a cell surface for CD24-induced cell type-specific effects on neurite and the importance of the intracellular signal of a cell type that determines neurite outgrowth or inhibition from cell surface we that the interaction L1 and and CD24-induced neurite outgrowth depends on the of acid on CD24. of CD24 from that the CD24 in the and not the with acid which are for binding of CD24 to These observations and the that the and with L1 in a the glycoform is in the raft (for a see Ref. Biol. 1998; PubMed Scopus Google that L1 acid on CD24 and as a in acid binding recognition molecules of the and nervous have been in the the the cell and (for a see Ref. S. R. 1997; PubMed Google Scholar, and for a see M. S. S. N. J. R. Schachner M. 1998; 8: Scholar). These a in the of the immunoglobulin that is by amino acids Ref. M. S. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar and and which the which only to The importance of a in the binding of acid has been reported for as S. B. 1998; 8: PubMed Scopus Google and the M. S. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google the of the a with the of The in is in the type of This is in of the L1 the of L1 and Ref. J. R. V. Bartsch U. M. H. D. Schachner M. Eur. J. Neurosci. 1996; 8: PubMed Scopus Google Scholar and The L1 to from the of adhesion molecules by the that the not the the for acid of a the and that the is of a A.J. 12: Full Text PDF PubMed Scopus Google together with the is highly within the L1 of and the of the to acid or in L1 from with and 1998; PubMed Scopus Google Scholar, U. J. B. J. Genet. PubMed Scopus Google Scholar). in or mice in the R. G. M. J. Soriano P. H. R. Lemmon V. Mol. Genet. 1998; 7: PubMed Scopus Google H. M. and M. or dorsal root (for in the of L1 see Ref. C. Lemmon J. J. Biol. PubMed Scopus Google Scholar). Interestingly, not recognition molecules show in the binding the and Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google the and which to the of R. C. M. M. U. S. 1995; PubMed Scopus Google the S. M. D. C. C. S. C. M. J. 1998; PubMed Scopus Google the R. 1997; PubMed Google and the B. S. B. B. R. R. M. P. G. PubMed Scopus Google Scholar). of molecules play in and It is that the cell adhesion that is in as a acid N. Faivre-Sarrailh C. J. Rougon G. C. J. 1998; Google which the binding of the to in from a with B. S. B. B. R. R. M. P. G. PubMed Scopus Google also to the acid binding The observations the importance of acid binding for nervous system binding of acid on CD24 to L1 is to play a functional role in neurite outgrowth. CD24 not neurite outgrowth of dorsal root ganglion neurons and neurite outgrowth of acid on L1 are not for binding to CD24 and promotion of neurite of L1 not with neurite and expressed L1 also neurite on a L1 from Ref. J. N. S. C. S. Schachner M. M. J. Neurobiol. PubMed Scopus Google Scholar and It is that the of L1 and CD24 together the of neurite outgrowth from an of neurite outgrowth of dorsal root ganglion and neurons to the of CD24 It is that CD24 with L1 in trans-interaction with L1 on It is also that binding of CD24 to L1 to a or to a of homophilic binding of L1 to the of L1 that the for cell binding and neurite outgrowth J. N. S. C. S. Schachner M. M. J. Neurobiol. PubMed Scopus Google Scholar). important for interaction has been for J. Biol. PubMed Scopus Google or G. Altevogt P. Schachner M. J. Biol. PubMed Scopus Google Scholar, R. Schachner M. B. B. Eur. J. Biol. 1998; PubMed Scopus Google Scholar). of in has been reported for which with its and These are the It has been that a cell type-specific of glycosylation a to in the nervous system (for see Ref. PubMed Scopus Google effects on neurite outgrowth of dorsal root ganglion or neurons by CD24 are by to L1 and are not neurons are from L1 knockout neurons from CD24 knockout mice are not different in neurite outgrowth from type These show that CD24 its neurite and effects via a trans-interaction with L1 at the cell surface and the that a homophilic interaction of CD24 the effects on neurite outgrowth. that the α2,3-sialic and are in trans-interaction with L1, which not only in the also in H. M. and M. These from by and with L1 in a membrane and are with L1 Interestingly, the α2,3-sialic glycoform from by with and it not with L1 in raft microdomains, it is to interact in or with L1 for L1 and CD24 The trans-interaction the and of CD24 and L1 depends on acid These could on neurons or L1 and the glycoform of CD24 are in different membrane L1 is in a membrane the glycoform of CD24 is within that CD24 is highly expressed in the where N.R. Taylor J.S. Scott L.B. Guillery R.W. Soriano P. Furley A.J. Curr. Biol. 1998; 8: 26-33Abstract Full Text Full Text PDF PubMed Scopus (337) Google that L1 and CD24 play a role in guidance as has been shown for the functional the extracellular and L1, which with the V. Schachner M. Faivre-Sarrailh C. Rougon G. Full Text Full Text PDF PubMed Scopus Google Scholar). of the of on neurons L1 as a together with These observations and the in the the that the inhibition or of neurite outgrowth could on the signal is different different cell types and depends on the different in the different cell in a different of in the of signal could or growth P. Neurobiol. 1996; Google or R. Schachner M. Eur. J. Neurosci. 1995; 7: PubMed Scopus Google The and of by could not only the also could to different of molecules, as L1, in with molecules, as CD24. The of the of and in of signal an for Path-finding of growth cones and neurite outgrowth toward targets are important events in the developing and regenerating nervous system and in synaptic remodeling during learning and memory. Axonal guidance depends on molecules at the cell surface and in the extracellular matrix. The different and often changing combinations of molecularly associated recognition molecules at the cell surface are important determinants of the ways by which the cell surface communicates with the cell interior, where cell surface signals are integrated to influence cell recognition molecules, L1 of the immunoglobulin superfamily and CD24, a highly glycosylated mucin type glycoprotein, interact with each other functionally (1Kadmon G. von Bohlen und Halbach F. Horstkorte R. Eckert M. Altevogt P. Schachner M. Eur. J. Neurosci. 1995; 7: 993-1004Crossref PubMed Scopus (56) Google Scholar, 2Sammar M. Aigner S. Altevogt P. Biochim. Biophys. Acta. 1997; 1337: 287-294Crossref PubMed Scopus (45) Google Scholar). L1 is a 200-kDa homophilic and heterophilic adhesion molecule expressed by many postmitotic neurons in the central nervous system (for reviews, see Refs. 3Brümmendorf T. Kenwrick S. Rathjen F.G. Curr. Opin. Neurobiol. 1998; 8: 87-97Crossref PubMed Scopus (212) Google Scholar and 4Kamiguchi H. Hlavin M.L. Lemmon V. Mol. Cell. Neurosci. 1998; 12: 48-55Crossref PubMed Scopus (116) Google Scholar). It is one of the most potent promoters of neurite outgrowth in vitro known so far. Mutants of L1 in mice and men strongly underscore its importance during embryonic development in vivo (3Brümmendorf T. Kenwrick S. Rathjen F.G. Curr. Opin. Neurobiol. 1998; 8: 87-97Crossref PubMed Scopus (212) Google Scholar, 5Dahme M. Bartsch U. Martini R. Anliker B. Schachner M. Mantei N. Nat. Genet. 1997; 17: 346-349Crossref PubMed Scopus (410) Google Scholar, 6Cohen N.R. Taylor J.S. Scott L.B. Guillery R.W. Soriano P. Furley A.J. Curr. Biol. 1998; 8: 26-33Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar). CD24 is linked to the surface membrane by a glycosyl phosphatidylinositol anchor and is, therefore, unable to directly interact with cytoplasmic proteins. It is also known as heat-stable antigen or nectadrin with a peptide core of only 30 amino acids (for references, see Ref. 1Kadmon G. von Bohlen und Halbach F. Horstkorte R. Eckert M. Altevogt P. Schachner M. Eur. J. Neurosci. 1995; 7: 993-1004Crossref PubMed Scopus (56) Google Scholar). Similar to L1, it is highly expressed by neurons (7Nédelec J. Pierres M. Moreau H. Barbet J. Naquet P. Faivre-Sarrailh C. Rougon G. Eur. J. Biochem. 1992; 203: 433-440Crossref PubMed Scopus (35) Google Scholar, 8Shewan D. Calaora V. Nielsen P. Cohen J. Rougon G. Moreau H. J. Neurosci. 1996; 16: 2624-2634Crossref PubMed Google Scholar). The apparent molecular weight of CD24 varies considerably among cell types and also within each cell type, depending on its developmental stage due to differences in glycosylation pattern (for references, see Refs. 1Kadmon G. von Bohlen und Halbach F. Horstkorte R. Eckert M. Altevogt P. Schachner M. Eur. J. Neurosci. 1995; 7: 993-1004Crossref PubMed Scopus (56) Google Scholar and 7Nédelec J. Pierres M. Moreau H. Barbet J. Naquet P. Faivre-Sarrailh C. Rougon G. Eur. J. Biochem. 1992; 203: 433-440Crossref PubMed Scopus (35) Google Scholar). These observations suggest that post-translational modifications of CD24 play an important functional role. CD24 acts as a co-stimulator for various physiological functions. In the nervous system, CD24 has been reported to interact with L1 to stimulate cell adhesion and to increase intracellular Ca2+levels (1Kadmon G. von Bohlen und Halbach F. Horstkorte R. Eckert M. Altevogt P. Schachner M. Eur. J. Neurosci. 1995; 7: 993-1004Crossref PubMed Scopus (56) Google Scholar, 2Sammar M. Aigner S. Altevogt P. Biochim. Biophys. Acta. 1997; 1337: 287-294Crossref PubMed Scopus (45) Google Scholar). Interestingly, CD24 has been shown to inhibit neurite outgrowth of neonatal retinal ganglion cells and dorsal root ganglion neurons in culture (8Shewan D. Calaora V. Nielsen P. Cohen J. Rougon G. Moreau H. J. Neurosci. 1996; 16: 2624-2634Crossref PubMed Google by signal on observations on the functional and molecular L1 and CD24, we to functional Here we report that L1 is a for CD24 and that CD24 neurite outgrowth of dorsal root ganglion neurons and neurite outgrowth of neurons via interaction in with L1 at the cell surface of the neurite to underscore important observations in cell the of as of recognition molecules in the of L1 as a and of the M. S. S. N. J. R. Schachner M. 1998; 8: in the type of the L1 the of L1 as a cell surface for CD24-induced cell type-specific effects on neurite and the importance of the intracellular signal of a cell type that determines neurite outgrowth or inhibition from cell surface we that the interaction L1 and and CD24-induced neurite outgrowth depends on the of acid on CD24. of CD24 from that the CD24 in the and not the with acid which are for binding of CD24 to These observations and the that the and with L1 in a the glycoform is in the raft (for a see Ref. Biol. 1998; PubMed Scopus Google that L1 acid on CD24 and as a in acid binding recognition molecules of the and nervous have been in the the the cell and (for a see Ref. S. R. 1997; PubMed Google Scholar, and for a see M. S. S. N. J. R. Schachner M. 1998; 8: Scholar). These a in the of the immunoglobulin that is by amino acids Ref. M. S. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar and and which the which only to The importance of a in the binding of acid has been reported for as S. B. 1998; 8: PubMed Scopus Google and the M. S. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google the of the a with the of The in is in the type of This is in of the L1 the of L1 and Ref. J. R. V. Bartsch U. M. H. D. Schachner M. Eur. J. Neurosci. 1996; 8: PubMed Scopus Google Scholar and The L1 to from the of adhesion molecules by the that the not the the for acid of a the and that the is of a A.J. 12: Full Text PDF PubMed Scopus Google together with the is highly within the L1 of and the of the to acid or in L1 from with and 1998; PubMed Scopus Google Scholar, U. J. B. J. Genet. PubMed Scopus Google Scholar). in or mice in the R. G. M. J. Soriano P. H. R. Lemmon V. Mol. Genet. 1998; 7: PubMed Scopus Google H. M. and M. or dorsal root (for in the of L1 see Ref. C. Lemmon J. J. Biol. PubMed Scopus Google Scholar). Interestingly, not recognition molecules show in the binding the and Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google the and which to the of R. C. M. M. U. S. 1995; PubMed Scopus Google the S. M. D. C. C. S. C. M. J. 1998; PubMed Scopus Google the R. 1997; PubMed Google and the B. S. B. B. R. R. M. P. G. PubMed Scopus Google Scholar). of molecules play in and It is that the cell adhesion that is in as a acid N. Faivre-Sarrailh C. J. Rougon G. C. J. 1998; Google which the binding of the to in from a with B. S. B. B. R. R. M. P. G. PubMed Scopus Google also to the acid binding The observations the importance of acid binding for nervous system binding of acid on CD24 to L1 is to play a functional role in neurite outgrowth. CD24 not neurite outgrowth of dorsal root ganglion neurons and neurite outgrowth of acid on L1 are not for binding to CD24 and promotion of neurite of L1 not with neurite and expressed L1 also neurite on a L1 from Ref. J. N. S. C. S. Schachner M. M. J. Neurobiol. PubMed Scopus Google Scholar and It is that the of L1 and CD24 together the of neurite outgrowth from an of neurite outgrowth of dorsal root ganglion and neurons to the of CD24 It is that CD24 with L1 in trans-interaction with L1 on It is also that binding of CD24 to L1 to a or to a of homophilic binding of L1 to the of L1 that the for cell binding and neurite outgrowth J. N. S. C. S. Schachner M. M. J. Neurobiol. PubMed Scopus Google Scholar). important for interaction has been for J. Biol. PubMed Scopus Google or G. Altevogt P. Schachner M. J. Biol. PubMed Scopus Google Scholar, R. Schachner M. B. B. Eur. J. Biol. 1998; PubMed Scopus Google Scholar). of in has been reported for which with its and These are the It has been that a cell type-specific of glycosylation a to in the nervous system (for see Ref. PubMed Scopus Google effects on neurite outgrowth of dorsal root ganglion or neurons by CD24 are by to L1 and are not neurons are from L1 knockout neurons from CD24 knockout mice are not different in neurite outgrowth from type These show that CD24 its neurite and effects via a trans-interaction with L1 at the cell surface and the that a homophilic interaction of CD24 the effects on neurite outgrowth. that the α2,3-sialic and are in trans-interaction with L1, which not only in the also in H. M. and M. These from by and with L1 in a membrane and are with L1 Interestingly, the α2,3-sialic glycoform from by with and it not with L1 in raft microdomains, it is to interact in or with L1 that CD24 is highly expressed in the where N.R. Taylor J.S. Scott L.B. Guillery R.W. Soriano P. Furley A.J. Curr. Biol. 1998; 8: 26-33Abstract Full Text Full Text PDF PubMed Scopus (337) Google that L1 and CD24 play a role in guidance as has been shown for the functional the extracellular and L1, which with the V. Schachner M. Faivre-Sarrailh C. Rougon G. Full Text Full Text PDF PubMed Scopus Google Scholar). of the of on neurons L1 as a together with These observations and the in the the that the inhibition or of neurite outgrowth could on the signal is different different cell types and depends on the different in the different cell in a different of in the of signal could or growth P. Neurobiol. 1996; Google or R. Schachner M. Eur. J. Neurosci. 1995; 7: PubMed Scopus Google The and of by could not only the also could to different of molecules, as L1, in with molecules, as CD24. The of the of and in of signal an for In we that the interaction L1 and and CD24-induced neurite outgrowth depends on the of acid on CD24. of CD24 from that the CD24 in the and not the with acid which are for binding of CD24 to These observations and the that the and with L1 in a the glycoform is in the raft (for a see Ref. Biol. 1998; PubMed Scopus Google that L1 acid on CD24 and as a in acid binding recognition molecules of the and nervous have been in the the the cell and (for a see Ref. S. R. 1997; PubMed Google Scholar, and for a see M. S. S. N. J. R. Schachner M. 1998; 8: Scholar). These a in the of the immunoglobulin that is by amino acids Ref. M. S. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar and and which the which only to The importance of a in the binding of acid has been reported for as S. B. 1998; 8: PubMed Scopus Google and the M. S. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google the of the a with the of The in is in the type of This is in of the L1 the of L1 and Ref. J. R. V. Bartsch U. M. H. D. Schachner M. Eur. J. Neurosci. 1996; 8: PubMed Scopus Google Scholar and The L1 to from the of adhesion molecules by the that the not the the for acid of a the and that the is of a A.J. 12: Full Text PDF PubMed Scopus Google together with the is highly within the L1 of and the of the to acid or in L1 from with and 1998; PubMed Scopus Google Scholar, U. J. B. J. Genet. PubMed Scopus Google Scholar). in or mice in the R. G. M. J. Soriano P. H. R. Lemmon V. Mol. Genet. 1998; 7: PubMed Scopus Google H. M. and M. or dorsal root (for in the of L1 see Ref. C. Lemmon J. J. Biol. PubMed Scopus Google Scholar). Interestingly, not recognition molecules show in the binding the and Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google the and which to the of R. C. M. M. U. S. 1995; PubMed Scopus Google the S. M. D. C. C. S. C. M. J. 1998; PubMed Scopus Google the R. 1997; PubMed Google and the B. S. B. B. R. R. M. P. G. PubMed Scopus Google Scholar). of molecules play in and It is that the cell adhesion that is in as a acid N. Faivre-Sarrailh C. J. Rougon G. C. J. 1998; Google which the binding of the to in from a with B. S. B. B. R. R. M. P. G. PubMed Scopus Google also to the acid binding The observations the importance of acid binding for nervous system The binding of acid on CD24 to L1 is to play a functional role in neurite outgrowth. CD24 not neurite outgrowth of dorsal root ganglion neurons and neurite outgrowth of acid on L1 are not for binding to CD24 and promotion of neurite of L1 not with neurite and expressed L1 also neurite on a L1 from Ref. J. N. S. C. S. Schachner M. M. J. Neurobiol. PubMed Scopus Google Scholar and It is that the of L1 and CD24 together the of neurite outgrowth from an of neurite outgrowth of dorsal root ganglion and neurons to the of CD24 It is that CD24 with L1 in trans-interaction with L1 on It is also that binding of CD24 to L1 to a or to a of homophilic binding of L1 to the of L1 that the for cell binding and neurite outgrowth J. N. S. C. S. Schachner M. M. J. Neurobiol. PubMed Scopus Google Scholar). important for interaction has been for J. Biol. PubMed Scopus Google or G. Altevogt P. Schachner M. J. Biol. PubMed Scopus Google Scholar, R. Schachner M. B. B. Eur. J. Biol. 1998; PubMed Scopus Google Scholar). of in has been reported for which with its and These are the It has been that a cell type-specific of glycosylation a to in the nervous system (for see Ref. PubMed Scopus Google Scholar). The effects on neurite outgrowth of dorsal root ganglion or neurons by CD24 are by to L1 and are not neurons are from L1 knockout neurons from CD24 knockout mice are not different in neurite outgrowth from type These show that CD24 its neurite and effects via a trans-interaction with L1 at the cell surface and the that a homophilic interaction of CD24 the effects on neurite outgrowth. that the α2,3-sialic and are in trans-interaction with L1, which not only in the also in H. M. and M. These from by and with L1 in a membrane and are with L1 Interestingly, the α2,3-sialic glycoform from by with and it not with L1 in raft microdomains, it is to interact in or with L1 The that CD24 is highly expressed in the where N.R. Taylor J.S. Scott L.B. Guillery R.W. Soriano P. Furley A.J. Curr. Biol. 1998; 8: 26-33Abstract Full Text Full Text PDF PubMed Scopus (337) Google that L1 and CD24 play a role in guidance as has been shown for the functional the extracellular and L1, which with the V. Schachner M. Faivre-Sarrailh C. Rougon G. Full Text Full Text PDF PubMed Scopus Google Scholar). of the of on neurons L1 as a together with These observations and the in the the that the inhibition or of neurite outgrowth could on the signal is different different cell types and depends on the different in the different cell in a different of in the of signal could or growth P. Neurobiol. 1996; Google or R. Schachner M. Eur. J. Neurosci. 1995; 7: PubMed Scopus Google The and of by could not only the also could to different of molecules, as L1, in with molecules, as CD24. The of the of and in of signal an for are to and for with and Nielsen for the L1 and CD24 mutants, for peptide and for and for on the

The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of β-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.