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Article ; Online: Tks5 SH3 domains exhibit differential effects on invadopodia development.

Daly, Christina / Logan, Brewer / Breeyear, Joseph / Whitaker, Kelley / Ahmed, Maryam / Seals, Darren F

PloS one

2020 Volume 15, Issue 1, Page(s) e0227855

Abstract: The Src substrate Tks5 helps scaffold matrix-remodeling invadopodia in invasive cancer cells. Focus was directed here on how the five SH3 domains of Tks5 impact that activity. Mutations designed to inhibit protein-protein interactions were created in the ...

Abstract	The Src substrate Tks5 helps scaffold matrix-remodeling invadopodia in invasive cancer cells. Focus was directed here on how the five SH3 domains of Tks5 impact that activity. Mutations designed to inhibit protein-protein interactions were created in the individual SH3 domains of Tks5, and the constructs were introduced into the LNCaP prostate carcinoma cell line, a model system with intrinsically low Tks5 expression and which our lab had previously showed the dependence of Src-dependent Tks5 phosphorylation on invadopodia development. In LNCaP cells, acute increases in wild-type Tks5 led to increased gelatin matrix degradation. A similar result was observed when Tks5 was mutated in its 4th or 5th SH3 domains. This was in contrast to the 1st, 2nd, and 3rd SH3 domain mutations of Tks5 where each had a remarkable accentuating effect on gelatin degradation. Conversely, in the invadopodia-competent Src-3T3 model system, mutations in any one of the first three SH3 domains had a dominant negative effect that largely eliminated the presence of invadopodia, inhibited gelatin degradation activity, and redistributed both Src, cortactin, and Tks5 to what are likely endosomal compartments. A hypothesis involving Tks5 conformational states and the regulation of endosomal trafficking is presented as an explanation for these seemingly disparate results.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/chemistry ; Adaptor Proteins, Vesicular Transport/genetics ; Carcinoma/genetics ; Carcinoma/metabolism ; Carcinoma/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; Cortactin/genetics ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Gelatin/genetics ; Gelatin/metabolism ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Male ; Mutation/genetics ; Phosphorylation ; Podosomes/genetics ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Protein Interaction Domains and Motifs/genetics ; src Homology Domains/genetics ; src-Family Kinases/genetics
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Cortactin ; SH3PXD2A protein, human ; Gelatin (9000-70-8) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2020-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0227855
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Article ; Online: Tks5 SH3 domains exhibit differential effects on invadopodia development.

Christina Daly / Brewer Logan / Joseph Breeyear / Kelley Whitaker / Maryam Ahmed / Darren F Seals

PLoS ONE, Vol 15, Iss 1, p e

2020 Volume 0227855

Abstract	The Src substrate Tks5 helps scaffold matrix-remodeling invadopodia in invasive cancer cells. Focus was directed here on how the five SH3 domains of Tks5 impact that activity. Mutations designed to inhibit protein-protein interactions were created in the individual SH3 domains of Tks5, and the constructs were introduced into the LNCaP prostate carcinoma cell line, a model system with intrinsically low Tks5 expression and which our lab had previously showed the dependence of Src-dependent Tks5 phosphorylation on invadopodia development. In LNCaP cells, acute increases in wild-type Tks5 led to increased gelatin matrix degradation. A similar result was observed when Tks5 was mutated in its 4th or 5th SH3 domains. This was in contrast to the 1st, 2nd, and 3rd SH3 domain mutations of Tks5 where each had a remarkable accentuating effect on gelatin degradation. Conversely, in the invadopodia-competent Src-3T3 model system, mutations in any one of the first three SH3 domains had a dominant negative effect that largely eliminated the presence of invadopodia, inhibited gelatin degradation activity, and redistributed both Src, cortactin, and Tks5 to what are likely endosomal compartments. A hypothesis involving Tks5 conformational states and the regulation of endosomal trafficking is presented as an explanation for these seemingly disparate results.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Oncolytic vesicular stomatitis viruses selectively target M2 macrophages.

Polzin, Megan / McCanless, Jessica / Owen, Sylas / Sizemore, Dalton / Lucero, Emily / Fuller, Rebecca / Neufeld, Howard S / Seals, Darren F / Ahmed, Maryam

Virus research

2020 Volume 284, Page(s) 197991

Abstract: Macrophages have been identified as key players within the tumor microenvironment, with classically (M1) and alternatively (M2) activated macrophages exhibiting anti-tumoral and pro-tumoral functions, respectively. The goal of this study was to determine ...

Abstract	Macrophages have been identified as key players within the tumor microenvironment, with classically (M1) and alternatively (M2) activated macrophages exhibiting anti-tumoral and pro-tumoral functions, respectively. The goal of this study was to determine the response of macrophage populations to infection with oncolytic vesicular stomatitis virus (VSV). THP-1 monocytes were differentiated into various macrophage subsets and infected with wild-type (rwt virus) or matrix (M) protein mutant (rM51R-M virus) strains of VSV. Monocytes and M2 macrophages were susceptible to infection and killing by both rwt and rM51R-M viruses. rM51R-M virus also increased expression of the M1 markers p-STAT1, CD80, and TNF-α in pro-tumoral M2 macrophages, suggesting reprogramming towards an M1-like pro-inflammatory state. Meanwhile, rwt virus was more effective than rM51R-M virus at replicating in M2 macrophages and at inhibiting the development of invasive podosome structures. This was all in contrast to anti-tumoral M1 macrophages, which remained resistant to VSV-induced cytopathic effects. These results indicate that macrophage populations are differentially susceptible to VSV and that rwt and rM51R-M viruses may modulate the tumor-promoting phenotype of M2 macrophages by distinct mechanisms.
MeSH term(s)	Cell Differentiation/immunology ; Humans ; Macrophages/classification ; Macrophages/immunology ; Macrophages/pathology ; Macrophages/virology ; Oncolytic Viruses/immunology ; Oncolytic Viruses/pathogenicity ; Podosomes/virology ; THP-1 Cells ; Vesiculovirus/immunology ; Vesiculovirus/pathogenicity
Language	English
Publishing date	2020-04-28
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2020.197991
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Article: Oncolytic vesicular stomatitis viruses selectively target M2 macrophages

Polzin, Megan / McCanless, Jessica / Owen, Sylas / Sizemore, Dalton / Lucero, Emily / Fuller, Rebecca / Neufeld, Howard S / Seals, Darren F / Ahmed, Maryam

Virus research. 2020 July 15, v. 284

2020

Abstract	Macrophages have been identified as key players within the tumor microenvironment, with classically (M1) and alternatively (M2) activated macrophages exhibiting anti-tumoral and pro-tumoral functions, respectively. The goal of this study was to determine the response of macrophage populations to infection with oncolytic vesicular stomatitis virus (VSV). THP-1 monocytes were differentiated into various macrophage subsets and infected with wild-type (rwt virus) or matrix (M) protein mutant (rM51R-M virus) strains of VSV. Monocytes and M2 macrophages were susceptible to infection and killing by both rwt and rM51R-M viruses. rM51R-M virus also increased expression of the M1 markers p-STAT1, CD80, and TNF-α in pro-tumoral M2 macrophages, suggesting reprogramming towards an M1-like pro-inflammatory state. Meanwhile, rwt virus was more effective than rM51R-M virus at replicating in M2 macrophages and at inhibiting the development of invasive podosome structures. This was all in contrast to anti-tumoral M1 macrophages, which remained resistant to VSV-induced cytopathic effects. These results indicate that macrophage populations are differentially susceptible to VSV and that rwt and rM51R-M viruses may modulate the tumor-promoting phenotype of M2 macrophages by distinct mechanisms.
Keywords	Vesiculovirus ; cytopathogenicity ; disease susceptibility ; macrophages ; monocytes ; mutants ; neoplasms ; phenotype ; tumor necrosis factor-alpha ; vesicular stomatitis ; viruses
Language	English
Dates of publication	2020-0715
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2020.197991
Database	NAL-Catalogue (AGRICOLA)

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Article: The ADAMs family of metalloproteases: multidomain proteins with multiple functions.

Seals, Darren F / Courtneidge, Sara A

Genes & development

2003 Volume 17, Issue 1, Page(s) 7–30

MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Adhesion Molecules/metabolism ; Cell Fusion ; Cell Lineage ; Cell Movement ; Cytokines/metabolism ; Fertilization ; Growth Substances/metabolism ; Humans ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/physiology ; Metalloendopeptidases/genetics ; Metalloendopeptidases/physiology ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Multigene Family ; Muscle Proteins/metabolism ; Neoplasm Proteins/physiology ; Nerve Tissue Proteins/metabolism ; Protein Structure, Tertiary ; Receptors, Cell Surface/metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Signal Transduction ; Zinc/physiology
Chemical Substances	Cell Adhesion Molecules ; Cytokines ; Growth Substances ; Membrane Glycoproteins ; Muscle Proteins ; Neoplasm Proteins ; Nerve Tissue Proteins ; Receptors, Cell Surface ; Metalloendopeptidases (EC 3.4.24.-) ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2003-01-01
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.1039703
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Article ; Online: The podosome marker protein Tks5 regulates macrophage invasive behavior.

Burger, Karen L / Davis, Amanda L / Isom, Scott / Mishra, Nilamadhab / Seals, Darren F

Cytoskeleton (Hoboken, N.J.)

2011 Volume 68, Issue 12, Page(s) 694–711

Abstract: ... these cells lose the ability to focalize F-actin and its accessory proteins into podosome-like structures ...

Abstract	Tks5 is a Src substrate and adaptor protein previously recognized for its regulation of cancer cell invasion through modulation of specialized adhesion structures called podosomes/invadopodia. Here we show for the first time that Tks5 localizes to the podosomes of primary macrophages, and that Tks5 protein levels increase concurrently with podosome deposition during the differentiation of monocytes into macrophages. Similar results are reported for model THP-1 cells, which differentiate into macrophages and form proteolytically active podosomes in response to a PKC signaling agonist (PMA) and with sensitivity to a PKC inhibitor (bisindolylmaleimide). Genetic manipulation of Tks5 expression (silencing and overexpression) in stable THP-1 cell lines does not independently alter this macrophage differentiation process. Nor do these cells lose the ability to focalize F-actin and its accessory proteins into podosome-like structures following PMA treatment. However, Tks5 directly controls podosome-associated gelatin degradation and invasion through collective changes in adhesion, chemotaxis, and the expression/proteolytic activity of MMP9. The Src family kinase-dependent phosphorylation of Tks5 is also implicated in the regulation of THP-1 macrophage invasive behavior. These results therefore define a previously unappreciated function of Tks5 signaling specific to the functional attributes of the macrophage podosome in adhesion, motility, and extracellular matrix-remodeling.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/blood ; Biomarkers/blood ; Cell Line, Tumor ; Cell Movement/physiology ; Humans ; Macrophages/cytology ; Macrophages/metabolism ; Phosphoproteins/metabolism ; Signal Transduction
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Biomarkers ; Phosphoproteins ; SH3PXD2A protein, human
Language	English
Publishing date	2011-11-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2534372-5
ISSN	1949-3592 ; 1949-3584
ISSN (online)	1949-3592
ISSN	1949-3584
DOI	10.1002/cm.20545
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Article ; Online: Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells.

Burger, Karen L / Learman, Brian S / Boucherle, Amy K / Sirintrapun, S Joseph / Isom, Scott / Díaz, Begoña / Courtneidge, Sara A / Seals, Darren F

The Prostate

2013 Volume 74, Issue 2, Page(s) 134–148

Abstract: Background: The Src tyrosine kinase substrate and adaptor protein Tks5 had previously been implicated in the invasive phenotype of normal and transformed cell types via regulation of cytoskeletal structures called podosomes/invadopodia. The role of Src- ... ...

Abstract	Background: The Src tyrosine kinase substrate and adaptor protein Tks5 had previously been implicated in the invasive phenotype of normal and transformed cell types via regulation of cytoskeletal structures called podosomes/invadopodia. The role of Src-Tks5 signaling in invasive prostate cancer, however, had not been previously evaluated. Methods: We measured the relative expression of Tks5 in normal (n = 20) and cancerous (n = 184, from 92 patients) prostate tissue specimens by immunohistochemistry using a commercially available tumor microarray. We also manipulated the expression and activity of wild-type and mutant Src and Tks5 constructs in the LNCaP and PC-3 prostate cancer cell lines in order to ascertain the role of Src-Tks5 signaling in invadopodia development, matrix-remodeling activity, motility, and invasion. Results: Our studies demonstrated that Src was activated and Tks5 upregulated in high Gleason score prostate tumor specimens and in invasive prostate cancer cell lines. Remarkably, overexpression of Tks5 in LNCaP cells was sufficient to induce invadopodia formation and associated matrix degradation. This Tks5-dependent increase in invasive behavior further depended on Src tyrosine kinase activity and the phosphorylation of Tks5 at tyrosine residues 557 and 619. In PC-3 cells we demonstrated that Tks5 phosphorylation at these sites was necessary and sufficient for invadopodia-associated matrix degradation and invasion. Conclusions: Our results suggest a general role for Src-Tks5 signaling in prostate tumor progression and the utility of Tks5 as a marker protein for the staging of this disease.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/physiology ; Adenocarcinoma/pathology ; Adenocarcinoma/physiopathology ; Biomarkers, Tumor/physiology ; Case-Control Studies ; Cell Line, Tumor ; Cell Movement/physiology ; Cytoskeleton/physiology ; Disease Progression ; Humans ; Immunohistochemistry ; Male ; Phosphorylation/physiology ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/physiopathology ; Signal Transduction/physiology ; src-Family Kinases/physiology
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Biomarkers, Tumor ; SH3PXD2A protein, human ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2013-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	604707-5
ISSN	1097-0045 ; 0270-4137
ISSN (online)	1097-0045
ISSN	0270-4137
DOI	10.1002/pros.22735
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Article ; Online: Metabolic regulation of invadopodia and invasion by acetyl-CoA carboxylase 1 and de novo lipogenesis.

Scott, Kristen E N / Wheeler, Frances B / Davis, Amanda L / Thomas, Michael J / Ntambi, James M / Seals, Darren F / Kridel, Steven J

PloS one

2012 Volume 7, Issue 1, Page(s) e29761

Abstract: Invadopodia are membrane protrusions that facilitate matrix degradation and cellular invasion. Although lipids have been implicated in several aspects of invadopodia formation, the contributions of de novo fatty acid synthesis and lipogenesis have not ... ...

Abstract	Invadopodia are membrane protrusions that facilitate matrix degradation and cellular invasion. Although lipids have been implicated in several aspects of invadopodia formation, the contributions of de novo fatty acid synthesis and lipogenesis have not been defined. Inhibition of acetyl-CoA carboxylase 1 (ACC1), the committed step of fatty acid synthesis, reduced invadopodia formation in Src-transformed 3T3 (3T3-Src) cells, and also decreased the ability to degrade gelatin. Inhibition of fatty acid synthesis through AMP-activated kinase (AMPK) activation and ACC phosphorylation also decreased invadopodia incidence. The addition of exogenous 16∶0 and 18∶1 fatty acid, products of de novo fatty acid synthesis, restored invadopodia and gelatin degradation to cells with decreased ACC1 activity. Pharmacological inhibition of ACC also altered the phospholipid profile of 3T3-Src cells, with the majority of changes occurring in the phosphatidylcholine (PC) species. Exogenous supplementation with the most abundant PC species, 34∶1 PC, restored invadopodia incidence, the ability to degrade gelatin and the ability to invade through matrigel to cells deficient in ACC1 activity. On the other hand, 30∶0 PC did not restore invadopodia and 36∶2 PC only restored invadopodia incidence and gelatin degradation, but not cellular invasion through matrigel. Pharmacological inhibition of ACC also reduced the ability of MDA-MB-231 breast, Snb19 glioblastoma, and PC-3 prostate cancer cells to invade through matrigel. Invasion of PC-3 cells through matrigel was also restored by 34∶1 PC supplementation. Collectively, the data elucidate the novel metabolic regulation of invadopodia and the invasive process by de novo fatty acid synthesis and lipogenesis.
MeSH term(s)	3T3 Cells ; Acetyl-CoA Carboxylase/antagonists & inhibitors ; Acetyl-CoA Carboxylase/genetics ; Acetyl-CoA Carboxylase/metabolism ; Acetyl-CoA Carboxylase/physiology ; Animals ; Cell Adhesion/drug effects ; Cell Adhesion/genetics ; Cell Movement/drug effects ; Cell Movement/genetics ; Cell Movement/physiology ; Cell Surface Extensions/drug effects ; Cell Surface Extensions/genetics ; Cell Surface Extensions/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, src/physiology ; Humans ; Lipogenesis/drug effects ; Lipogenesis/genetics ; Lipogenesis/physiology ; Male ; Mice ; Neoplasm Invasiveness ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; RNA, Small Interfering/pharmacology ; Tumor Cells, Cultured
Chemical Substances	RNA, Small Interfering ; Acetyl-CoA Carboxylase (EC 6.4.1.2)
Language	English
Publishing date	2012-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0029761
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Article ; Online: The anti-angiogenic and cytotoxic effects of the boswellic acid analog BA145 are potentiated by autophagy inhibitors.

Pathania, Anup S / Wani, Zahoor A / Guru, Santosh K / Kumar, Suresh / Bhushan, Shashi / Korkaya, Hasan / Seals, Darren F / Kumar, Ajay / Mondhe, Dilip M / Ahmed, Zabeer / Chandan, Bal K / Malik, Fayaz

Molecular cancer

2015 Volume 14, Page(s) 6

Abstract: Background: While angiogenesis inhibitors represent a viable cancer therapy, there is preclinical and clinical data to suggest that many tumors develop resistance to such treatments. Moreover, previous studies have revealed a complex association between ...

Abstract	Background: While angiogenesis inhibitors represent a viable cancer therapy, there is preclinical and clinical data to suggest that many tumors develop resistance to such treatments. Moreover, previous studies have revealed a complex association between autophagy and angiogenesis, and their collective influence on tumorigenesis. Autophagy has been implicated in cytoprotection and tumor promotion, and as such may represent an alternative way of targeting apoptosis-resistant cancer cells. This study explored the anti-cancer agent and boswellic acid analog BA145 as an inducer of autophagy and angiogenesis-mediated cytoprotection of tumor cells. Methods: Flow cytometry, western blotting, and confocal microscopy were used to investigate the role of BA145 mediated autophagy. ELISA, microvessel sprouting, capillary structure formation, aortic ring and wound healing assays were performed to determine the relationship between BA145 triggered autophagy and angiogenesis. Flow cytometery, western blotting, and microscopy were employed to examine the mechanism of BA145 induced cell death and apoptosis. Live imaging and tumor volume analysis were carried out to evaluate the effect of BA145 triggered autophagy on mouse tumor xenografts. Results: BA145 induced autophagy in PC-3 cancer cells and HUVECs significantly impeded its negative regulation on cell proliferation, migration, invasion and tube formation. These effects of BA145 induced autophagy were observed under both normoxic and hypoxic conditions. However, inhibition of autophagy using either pharmacological inhibitors or RNA interference enhanced the BA145 mediated death of these cells. Similar observations were noticed with sunitinib, the anti-angiogenic properties of which were significantly enhanced during combination treatments with autophagy inhibitors. In mouse tumor xenografts, co-treatment with chloroquinone and BA145 led to a considerable reduction in tumor burden and angiogenesis compared to BA145 alone. Conclusion: These studies reveal the essential role of BA145 triggered autophagy in the regulation of angiogenesis and cytoprotection. It also suggests that the combination of the autophagy inhibitors with chemotherapy or anti-angiogenic agents may be an effective therapeutic approach against cancer.
MeSH term(s)	Angiogenesis Inhibitors/pharmacology ; Animals ; Apoptosis/drug effects ; Autophagy/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Human Umbilical Vein Endothelial Cells ; Humans ; Indoles/pharmacology ; Pyrroles/pharmacology ; Triterpenes/chemistry
Chemical Substances	Angiogenesis Inhibitors ; Indoles ; Pyrroles ; Triterpenes ; boswellic acid (631-69-6) ; sunitinib (V99T50803M)
Language	English
Publishing date	2015-01-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1476-4598
ISSN (online)	1476-4598
DOI	10.1186/1476-4598-14-6
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Article: A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo.

Blouw, Barbara / Seals, Darren F / Pass, Ian / Diaz, Begoña / Courtneidge, Sara A

European journal of cell biology

2008 Volume 87, Issue 8-9, Page(s) 555–567

Abstract: Podosomes and invadopodia are electron-dense, actin-rich protrusions located on the ventral side of the cellular membrane. They are detected in various types of normal cells, but also in human cancer cells and in Src-transformed fibroblasts. Previously ... ...

Abstract	Podosomes and invadopodia are electron-dense, actin-rich protrusions located on the ventral side of the cellular membrane. They are detected in various types of normal cells, but also in human cancer cells and in Src-transformed fibroblasts. Previously we have shown that the scaffold protein Tks5 (tyrosine kinase substrate 5) co-localizes to podosomes/invadopodia in different human cancer cells and in Src-transformed NIH-3T3 cells. Upon reduced expression of Tks5 podosome formation is decreased, which leads to diminished gelatin degradation in vitro in various human cancer cell lines. It is unclear, however, whether cancer cells need podosomes for tumor growth and metastasis in vivo. To test this idea, we evaluated the ability of Src-transformed NIH-3T3 cells, showing stable reduced expression of Tks5 and podosome formation (Tks5 KD), to form subcutaneous tumors in mice. We demonstrate that decreased expression of Tks5 correlated with reduced tumor growth at this site. In addition, we generated lung metastases from these cells following tail vein injection. The lungs of mice injected i.v. with the Tks5 KD showed smaller-sized metastases, but there was no difference in the number of lesions compared to the controls, indicating that podosomes may not be required for extravasation from the blood stream into the lung parenchyma. Independent of the microenvironment however, the reduced tumor growth correlated with decreased tumor vascularization. Our data potentially implicate a novel role of podosomes as mediators of tumor angiogenesis and support further exploration of how podosome formation and Tks5 expression contribute to tumor progression.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/metabolism ; Animals ; Cell Line, Tumor ; Cell Surface Extensions/chemistry ; Humans ; Immunohistochemistry ; Mice ; Microfilament Proteins/metabolism ; Microfilament Proteins/physiology ; NIH 3T3 Cells ; Neoplasms/blood supply ; Neoplasms/metabolism ; Neoplasms/pathology ; Neovascularization, Pathologic ; Phosphate-Binding Proteins ; Phosphoproteins/metabolism ; Phosphoproteins/physiology ; Transfection ; src Homology Domains
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Fish protein, mouse ; Microfilament Proteins ; Phosphate-Binding Proteins ; Phosphoproteins ; SH3PXD2A protein, human
Language	English
Publishing date	2008-04-15
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391967-5
ISSN	1618-1298 ; 0171-9335 ; 0070-2463
ISSN (online)	1618-1298
ISSN	0171-9335 ; 0070-2463
DOI	10.1016/j.ejcb.2008.02.008
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