Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts

S. M. Goicoechea, R. García-Mata, J. Staub, A. Valdivia, L. Sharek, C. G. Mcculloch, R. F. Hwang, R. Urrutia, J. J. Yeh, H. J. Kim, C. A. Otey

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

The stromal compartment surrounding epithelial-derived pancreatic tumors is thought to have a key role in the aggressive phenotype of this malignancy. Emerging evidence suggests that cancer-associated fibroblasts (CAFs), the most abundant cells in the stroma of pancreatic tumors, contribute to the tumor's invasion, metastasis and resistance to therapy, but the precise molecular mechanisms that regulate CAFs behavior are poorly understood. In this study, we utilized immortalized human pancreatic CAFs to investigate molecular pathways that control the matrix-remodeling and invasion-promoting activity of CAFs. We showed previously that palladin, an actin-associated protein, is expressed at high levels in CAFs of pancreatic tumors and other solid tumors, and also in an immortalized line of human CAFs. In this study, we found that short-term exposure of CAFs to phorbol esters reduced the number of stress fibers and triggered the appearance of individual invadopodia and invadopodial rosettes in CAFs. Molecular analysis of invadopodia revealed that their composition resembled that of similar structures (that is, invadopodia and podosomes) described in other cell types. Pharmacological inhibition and small interfering RNA knockdown experiments demonstrated that protein kinase C, the small GTPase Cdc42 and palladin were necessary for the efficient assembly of invadopodia by CAFs. In addition, GTPase activity assays showed that palladin contributes to the activation of Cdc42. In mouse xenograft experiments using a mixture of CAFs and tumor cells, palladin expression in CAFs promoted the rapid growth and metastasis of human pancreatic tumor cells. Overall, these results indicate that high levels of palladin expression in CAFs enhance their ability to remodel the extracellular matrix by regulating the activity of Cdc42, which in turn promotes the assembly of matrix-degrading invadopodia in CAFs and tumor cell invasion. Together, these results identify a novel molecular signaling pathway that may provide new molecular targets for the inhibition of pancreatic cancer metastasis.

Original languageEnglish (US)
Pages (from-to)1265-1273
Number of pages9
JournalOncogene
Volume33
Issue number10
DOIs
StatePublished - 2014

Fingerprint

Pancreatic Neoplasms
Neoplasms
Neoplasm Metastasis
Cancer-Associated Fibroblasts
Podosomes
Stress Fibers
Aptitude
Monomeric GTP-Binding Proteins
GTP Phosphohydrolases
Phorbol Esters
Heterografts
Protein Kinase C
Small Interfering RNA
Extracellular Matrix
Actins
Pharmacology
Phenotype

Keywords

  • actin
  • Cdc42
  • GTPases
  • invadopodia
  • invasion
  • myofibroblasts

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Goicoechea, S. M., García-Mata, R., Staub, J., Valdivia, A., Sharek, L., Mcculloch, C. G., ... Otey, C. A. (2014). Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts. Oncogene, 33(10), 1265-1273. https://doi.org/10.1038/onc.2013.68

Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts. / Goicoechea, S. M.; García-Mata, R.; Staub, J.; Valdivia, A.; Sharek, L.; Mcculloch, C. G.; Hwang, R. F.; Urrutia, R.; Yeh, J. J.; Kim, H. J.; Otey, C. A.

In: Oncogene, Vol. 33, No. 10, 2014, p. 1265-1273.

Research output: Contribution to journalArticle

Goicoechea, SM, García-Mata, R, Staub, J, Valdivia, A, Sharek, L, Mcculloch, CG, Hwang, RF, Urrutia, R, Yeh, JJ, Kim, HJ & Otey, CA 2014, 'Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts', Oncogene, vol. 33, no. 10, pp. 1265-1273. https://doi.org/10.1038/onc.2013.68
Goicoechea, S. M. ; García-Mata, R. ; Staub, J. ; Valdivia, A. ; Sharek, L. ; Mcculloch, C. G. ; Hwang, R. F. ; Urrutia, R. ; Yeh, J. J. ; Kim, H. J. ; Otey, C. A. / Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts. In: Oncogene. 2014 ; Vol. 33, No. 10. pp. 1265-1273.
@article{bd8f3e3175c248b6899c64c73367f23b,
title = "Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts",
abstract = "The stromal compartment surrounding epithelial-derived pancreatic tumors is thought to have a key role in the aggressive phenotype of this malignancy. Emerging evidence suggests that cancer-associated fibroblasts (CAFs), the most abundant cells in the stroma of pancreatic tumors, contribute to the tumor's invasion, metastasis and resistance to therapy, but the precise molecular mechanisms that regulate CAFs behavior are poorly understood. In this study, we utilized immortalized human pancreatic CAFs to investigate molecular pathways that control the matrix-remodeling and invasion-promoting activity of CAFs. We showed previously that palladin, an actin-associated protein, is expressed at high levels in CAFs of pancreatic tumors and other solid tumors, and also in an immortalized line of human CAFs. In this study, we found that short-term exposure of CAFs to phorbol esters reduced the number of stress fibers and triggered the appearance of individual invadopodia and invadopodial rosettes in CAFs. Molecular analysis of invadopodia revealed that their composition resembled that of similar structures (that is, invadopodia and podosomes) described in other cell types. Pharmacological inhibition and small interfering RNA knockdown experiments demonstrated that protein kinase C, the small GTPase Cdc42 and palladin were necessary for the efficient assembly of invadopodia by CAFs. In addition, GTPase activity assays showed that palladin contributes to the activation of Cdc42. In mouse xenograft experiments using a mixture of CAFs and tumor cells, palladin expression in CAFs promoted the rapid growth and metastasis of human pancreatic tumor cells. Overall, these results indicate that high levels of palladin expression in CAFs enhance their ability to remodel the extracellular matrix by regulating the activity of Cdc42, which in turn promotes the assembly of matrix-degrading invadopodia in CAFs and tumor cell invasion. Together, these results identify a novel molecular signaling pathway that may provide new molecular targets for the inhibition of pancreatic cancer metastasis.",
keywords = "actin, Cdc42, GTPases, invadopodia, invasion, myofibroblasts",
author = "Goicoechea, {S. M.} and R. Garc{\'i}a-Mata and J. Staub and A. Valdivia and L. Sharek and Mcculloch, {C. G.} and Hwang, {R. F.} and R. Urrutia and Yeh, {J. J.} and Kim, {H. J.} and Otey, {C. A.}",
year = "2014",
doi = "10.1038/onc.2013.68",
language = "English (US)",
volume = "33",
pages = "1265--1273",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts

AU - Goicoechea, S. M.

AU - García-Mata, R.

AU - Staub, J.

AU - Valdivia, A.

AU - Sharek, L.

AU - Mcculloch, C. G.

AU - Hwang, R. F.

AU - Urrutia, R.

AU - Yeh, J. J.

AU - Kim, H. J.

AU - Otey, C. A.

PY - 2014

Y1 - 2014

N2 - The stromal compartment surrounding epithelial-derived pancreatic tumors is thought to have a key role in the aggressive phenotype of this malignancy. Emerging evidence suggests that cancer-associated fibroblasts (CAFs), the most abundant cells in the stroma of pancreatic tumors, contribute to the tumor's invasion, metastasis and resistance to therapy, but the precise molecular mechanisms that regulate CAFs behavior are poorly understood. In this study, we utilized immortalized human pancreatic CAFs to investigate molecular pathways that control the matrix-remodeling and invasion-promoting activity of CAFs. We showed previously that palladin, an actin-associated protein, is expressed at high levels in CAFs of pancreatic tumors and other solid tumors, and also in an immortalized line of human CAFs. In this study, we found that short-term exposure of CAFs to phorbol esters reduced the number of stress fibers and triggered the appearance of individual invadopodia and invadopodial rosettes in CAFs. Molecular analysis of invadopodia revealed that their composition resembled that of similar structures (that is, invadopodia and podosomes) described in other cell types. Pharmacological inhibition and small interfering RNA knockdown experiments demonstrated that protein kinase C, the small GTPase Cdc42 and palladin were necessary for the efficient assembly of invadopodia by CAFs. In addition, GTPase activity assays showed that palladin contributes to the activation of Cdc42. In mouse xenograft experiments using a mixture of CAFs and tumor cells, palladin expression in CAFs promoted the rapid growth and metastasis of human pancreatic tumor cells. Overall, these results indicate that high levels of palladin expression in CAFs enhance their ability to remodel the extracellular matrix by regulating the activity of Cdc42, which in turn promotes the assembly of matrix-degrading invadopodia in CAFs and tumor cell invasion. Together, these results identify a novel molecular signaling pathway that may provide new molecular targets for the inhibition of pancreatic cancer metastasis.

AB - The stromal compartment surrounding epithelial-derived pancreatic tumors is thought to have a key role in the aggressive phenotype of this malignancy. Emerging evidence suggests that cancer-associated fibroblasts (CAFs), the most abundant cells in the stroma of pancreatic tumors, contribute to the tumor's invasion, metastasis and resistance to therapy, but the precise molecular mechanisms that regulate CAFs behavior are poorly understood. In this study, we utilized immortalized human pancreatic CAFs to investigate molecular pathways that control the matrix-remodeling and invasion-promoting activity of CAFs. We showed previously that palladin, an actin-associated protein, is expressed at high levels in CAFs of pancreatic tumors and other solid tumors, and also in an immortalized line of human CAFs. In this study, we found that short-term exposure of CAFs to phorbol esters reduced the number of stress fibers and triggered the appearance of individual invadopodia and invadopodial rosettes in CAFs. Molecular analysis of invadopodia revealed that their composition resembled that of similar structures (that is, invadopodia and podosomes) described in other cell types. Pharmacological inhibition and small interfering RNA knockdown experiments demonstrated that protein kinase C, the small GTPase Cdc42 and palladin were necessary for the efficient assembly of invadopodia by CAFs. In addition, GTPase activity assays showed that palladin contributes to the activation of Cdc42. In mouse xenograft experiments using a mixture of CAFs and tumor cells, palladin expression in CAFs promoted the rapid growth and metastasis of human pancreatic tumor cells. Overall, these results indicate that high levels of palladin expression in CAFs enhance their ability to remodel the extracellular matrix by regulating the activity of Cdc42, which in turn promotes the assembly of matrix-degrading invadopodia in CAFs and tumor cell invasion. Together, these results identify a novel molecular signaling pathway that may provide new molecular targets for the inhibition of pancreatic cancer metastasis.

KW - actin

KW - Cdc42

KW - GTPases

KW - invadopodia

KW - invasion

KW - myofibroblasts

UR - http://www.scopus.com/inward/record.url?scp=84895922145&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895922145&partnerID=8YFLogxK

U2 - 10.1038/onc.2013.68

DO - 10.1038/onc.2013.68

M3 - Article

C2 - 23524582

AN - SCOPUS:84895922145

VL - 33

SP - 1265

EP - 1273

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 10

ER -