Assistant Professor
The Marvin and Concetta Greenberg Pancreatic Cancer Institute
As a member of the Marvin & Concetta Greenberg Pancreatic Cancer Institute, our lab focuses on the K-Ras oncogene and its signaling in pancreatic ductal adenocarcinoma (PDAC). While K-Ras is commonly hyperactivated (by mutation or extrinsic upstream signaling) in many cancer subtypes, and activating mutations occur in approximately 95% of PDAC cases, it remains a largely intractable target pharmacologically-speaking. Although novel mutation-specific K-Ras inhibitors are currently in clinical trials, their K-Ras G12C target is infrequent (~2%) in PDAC. As such, we are investigating the signaling cascades driven by K-Ras function to illuminate potential therapeutic targets.
Our research revolves around understanding how the Ras family of small GTPases impinges upon tumor invasion and metastasis, specifically in pancreatic ductal cancer. Ras is a nodal point of signaling, with input and activation from a wide range of stimuli including receptor tyrosine kinases, G protein-coupled receptors, integrins and extracellular matrix interactions, and chemokines. Once activated, Ras in turn triggers several signaling cascades that lead to a variety of transformed phenotypes including loss of cell cycle control, decreased cell death, and metastatic spread. Of particular interest to my lab is delineating how Ras activation in epithelial tumor cells drives signaling crosstalk to other compartments of the tumor microenvironment including stromal fibroblasts, macrophages, and vascular components. Paracrine signaling among these disparate cell populations likely contributes to protection of epithelial cells from cell cycle arrest, apoptosis, and senescence, as well as facilitating dedifferentiation and EMT.
At the same time that crosstalk affects the epithelial cells, there is evidence that aberrant activation of Ras leads to changes in extracellular matrix (ECM). Reorganization and dissolution of ECM by proteases and other enzymes accelerates cell migration for locoregional invasion and distal metastasis. In addition to Ras effects on the ECM architecture, we have recently shown that activation of this family of GTPases in pancreatic cancer leads to expression and secretion of CXC chemokines that is in part MAP kinase dependent. Vascular endothelial cells are sensitive to these chemokines via CXCR2 receptors, and respond by showing increased migration, invasion, and organization into vessel precursors. This angiogenesis may provide not only a means to nourish nascent tumors, but also serve as a conduit for malignant spread. As a result, we are interested in testing the hypothesis that small molecule inhibitors of the CXC-CXCR signaling axis may reduce the invasion and metastasis of pancreatic cancer and/or the expansion of already disseminated micrometastases.
Pancreatic cancer is also characterized by having an extensive stromal component. It is hypothesized that this bulk of fibroid tissue may be one of the reasons pancreatic cancer remains particularly insensitive to chemotherapeutic agents. Another arm of our research attempts to investigate whether tumor fibroblasts, like vascular endothelial cells, are responsive to CXC-CXCR crosstalk signaling triggered initially by epithelial K-Ras activation.
It is well established that mutational activation of K-Ras occurs very early in pancreatic ductal dysplasia and remains an important signaling impetus through the development of malignancy. We are investigating whether the signaling crosstalk between Ras and CXC chemokines is similarly triggered early in cancer progression by screening patient samples of initial dysplasia (pancreatic intraepithelial neoplasia, PanIN) to frank adenocarcinoma. By understanding the progression this signaling, we hope to uncover biomarkers to be used for screening and earlier detection.
Our research revolves around understanding how the Ras family of small GTPases impinges upon tumor invasion and metastasis, specifically in pancreatic ductal cancer. Ras is a nodal point of signaling, with input and activation from a wide range of stimuli including receptor tyrosine kinases, G protein-coupled receptors, integrins and extracellular matrix interactions, and chemokines. Once activated, Ras in turn triggers several signaling cascades that lead to a variety of transformed phenotypes including loss of cell cycle control, decreased cell death, and metastatic spread. Of particular interest to my lab is delineating how Ras activation in epithelial tumor cells drives signaling crosstalk to other compartments of the tumor microenvironment including stromal fibroblasts, macrophages, and vascular components. Paracrine signaling among these disparate cell populations likely contributes to protection of epithelial cells from cell cycle arrest, apoptosis, and senescence, as well as facilitating dedifferentiation and a hallmark of tumor progression and metastasis, epithelial-mesenchymal transition (EMT).
At the same time that crosstalk affects the epithelial cells, there is evidence that aberrant activation of Ras leads to changes in extracellular matrix (ECM). Reorganization and dissolution of ECM by proteases and other enzymes accelerates cell migration for locoregional invasion and distal metastasis. In addition to Ras effects on the ECM architecture, we have recently shown that activation of this family of GTPases in pancreatic cancer leads to expression and secretion of CXC chemokines that is in part MAP kinase-dependent. Vascular endothelial cells are sensitive to these chemokines via CXCR2 receptors, and respond by showing increased migration, invasion, and organization into vessel precursors. This angiogenesis may provide not only a means to nourish nascent tumors, but also serve as a conduit for malignant spread. As a result, we are interested in testing the hypothesis that small molecule inhibitors of the CXC-CXCR signaling axis may reduce the invasion and metastasis of pancreatic cancer and/or the expansion of already disseminated micrometastases.
Pancreatic cancer is also characterized by having an extensive stromal component. It is hypothesized that this bulk of fibroid tissue may be one of the reasons pancreatic cancer remains particularly insensitive to chemotherapeutic agents. Another arm of our research attempts to investigate whether tumor fibroblasts, like vascular endothelial cells, are responsive to CXC-CXCR crosstalk signaling triggered initially by epithelial K-Ras activation. It is well established that mutational activation of K-Ras occurs very early in pancreatic ductal dysplasia and remains an important signaling impetus through the development of malignancy. We are investigating whether the signaling crosstalk between Ras and CXC chemokines is similarly triggered early in cancer progression by screening patient samples of initial dysplasia (pancreatic intraepithelial neoplasia, PanIN) to frank adenocarcinoma. By understanding the progression this signaling, we hope to uncover biomarkers to be used for screening and earlier detection.
Finally, some of our recent work has demonstrated an interaction between K-Ras and the RNA-binding protein, HuR. Current investigations are looking at how K-Ras activation via genetic mutation influences HuR function and regulation of the cancer progression transcriptome, and in turn, how HuR governs K-Ras-dependent signaling in tumor epithelial cells.
A. Thadi, W.F. Morano, M. Khalili, B.B. Babcock, M.F. Shaikh, D.S. Foster, Y. Piazza, E.M. Gleeson, E. Goldstein, L. Steele, P.M. Campbell, B. Lin, M.R. Pincus, W.B. Bowne. 2021. Molecular targeting of H/MDM-2 oncoprotein in human colon cancer cells and stem-like colonic epithelial derived progenitor cells. Anticancer Res, 41:27-42. Pubmed.
Sliker B.H. and Campbell P.M. 2020. Ras and Ras Signaling as a therapeutic target in cancer. In Comprehensive Pharmacology, Terry Kenakin, Ph.D., editor, in press.
A. Thadi, E.M. Gleeson, M. Khalili, M.F. Shaikh, E. Goldstein, W.F. Morano, L.M. Daniels, N. Grandhi, H. Glatthorn, S.D. Richard, P.M. Campbell, M.R. Pincus, W.B. Bowne. 2020. Anti-cancer tumor cell necrosis of multidrug resistant ovarian cancer cell lines depends on high expression of HDM-2 protein in their membranes. Ann Clin Lab Sci, 50:611-624. Pubmed
A. Thadi, L. Lewis, E. Goldstein, A. Aggarwal, M. Khalili, L. Steele, B. Polyak, S. Seydafkan, M.H. Bluth, K.A. Ward, M. Styler, P.M. Campbell, M.R. Pincus, W.B. Bowne. 2020. Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells but Not Normal Hematopoietic Cells. Anticancer Res, 40:4857-4867. Pubmed
M.C. Stout and P.M. Campbell. 2018. RASpecting the oncogene: New pathways to therapeutic advances. Biochem Pharm, 158: 217-228. Pubmed
M.C. Stout, S. Narayan, E.S. Pillet, J.S. Salvino, P.M. Campbell. 2018. Inhibition of CX3CR1 Reduces Cell Motility and Viability in Pancreatic Adenocarcinoma Epithelial Cells. Biochem Biophys Res Commun, 495:2264– 2269. PubMed
S. Lal*, E. Cheung*, M. Zarei*, R. Preet, S.N. Chand, N.C. Mambelli-Lisboa, C. Romeo, M.C. Stout, E. Londin, A. Goetz, C. Yabar, A. Nevler, C.J. Yeo, P.M. Campbell, J.M. Winter, D.A. Dixon, J.R. Brody. 2017. CRISPR knockout of the HuR gene in pancreatic and colorectal cancer cells causes a xenograft lethal phenotype. * Contributed equally. Mol Cancer Res, 15:696-707. PubMed
M.C. Stout, E. Asiimwe, J.R. Birkenstamm, S.Y. Kim, P.M. Campbell. 2014. Analyzing Ras-associated Cell Proliferation Signaling. Methods Mol Biol, 1170:393-409. PubMed
P.M. Campbell. 2014. Oncogenic Ras pushes (and pulls) cell cycle progression through ERK activation. Methods Mol Biol, 1170:155-163. PubMed
H.R. Siddique, D.J. Liao, S.K. Mishra, T. Schuster, L. Wang, B. Matter, P.M. Campbell, P. Villalta, S. Nanda, Y. Deng, M. Saleem. 2012. Epicatechin-rich cocoa polyphenol inhibits Kras-activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model. Int J Cancer, 131:1720–1731. PubMed
J.J. Yeh, J.P. Madigan, P.M. Campbell, P.J. Roberts, L.M. DeGraffrenreid, C.J. Der. 2011. Targeting Ras for anti-cancer drug discovery. In Intercellular Signaling in Development and Disease, E.A. Dennis and R.A. Bradshaw, eds. Elsevier Press, pp. 335-355.
P.M. Campbell*, N. Boufaied*, J.J. Fiordalisi, A.D. Cox, P. Falardeau, C.J. Der, H. Gourdeau. 2010. TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-MAPK signaling. J Mol Signal, 5:18. * Contributed equally PubMed
Y. Matsuo*, P.M. Campbell*, R.A. Brekken, B. Sung, M.M. Ouellette, J.B. Fleming, B.B. Aggarwal, C.J. Der, S. Guha. 2009. K-Ras promotes angiogenesis mediated by immortalized human pancreatic epithelial cells through MAP kinase signaling pathways. Mol Cancer Res, 7:799-808. * Contributed equally. PubMed
P.M. Campbell, K.M. Lee, M.M. Ouellette, H.J. Kim, A.L. Groehler, V. Khazak, C.J. Der. 2008. Ras-driven transformation of human nestin-positive pancreatic epithelial cells. Methods Enzymol 439:451-65. PubMed
P.M. Campbell, A.L. Groehler, K.M. Lee, M.M. Ouellette, V. Khazak, C.J. Der. 2007. K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by Raf and phosphatidylinositol 3-kinase signaling. Cancer Res 67:2098-2106. PubMed
Paul.Campbell@fccc.edu
Office Phone: 215-728-2211
Office: W463
Paul.Campbell@fccc.edu
Office Phone: 215-728-2211
Office: W463
Assistant Professor
The Marvin and Concetta Greenberg Pancreatic Cancer Institute
As a member of the Marvin & Concetta Greenberg Pancreatic Cancer Institute, our lab focuses on the K-Ras oncogene and its signaling in pancreatic ductal adenocarcinoma (PDAC). While K-Ras is commonly hyperactivated (by mutation or extrinsic upstream signaling) in many cancer subtypes, and activating mutations occur in approximately 95% of PDAC cases, it remains a largely intractable target pharmacologically-speaking. Although novel mutation-specific K-Ras inhibitors are currently in clinical trials, their K-Ras G12C target is infrequent (~2%) in PDAC. As such, we are investigating the signaling cascades driven by K-Ras function to illuminate potential therapeutic targets.
Our research revolves around understanding how the Ras family of small GTPases impinges upon tumor invasion and metastasis, specifically in pancreatic ductal cancer. Ras is a nodal point of signaling, with input and activation from a wide range of stimuli including receptor tyrosine kinases, G protein-coupled receptors, integrins and extracellular matrix interactions, and chemokines. Once activated, Ras in turn triggers several signaling cascades that lead to a variety of transformed phenotypes including loss of cell cycle control, decreased cell death, and metastatic spread. Of particular interest to my lab is delineating how Ras activation in epithelial tumor cells drives signaling crosstalk to other compartments of the tumor microenvironment including stromal fibroblasts, macrophages, and vascular components. Paracrine signaling among these disparate cell populations likely contributes to protection of epithelial cells from cell cycle arrest, apoptosis, and senescence, as well as facilitating dedifferentiation and EMT.
At the same time that crosstalk affects the epithelial cells, there is evidence that aberrant activation of Ras leads to changes in extracellular matrix (ECM). Reorganization and dissolution of ECM by proteases and other enzymes accelerates cell migration for locoregional invasion and distal metastasis. In addition to Ras effects on the ECM architecture, we have recently shown that activation of this family of GTPases in pancreatic cancer leads to expression and secretion of CXC chemokines that is in part MAP kinase dependent. Vascular endothelial cells are sensitive to these chemokines via CXCR2 receptors, and respond by showing increased migration, invasion, and organization into vessel precursors. This angiogenesis may provide not only a means to nourish nascent tumors, but also serve as a conduit for malignant spread. As a result, we are interested in testing the hypothesis that small molecule inhibitors of the CXC-CXCR signaling axis may reduce the invasion and metastasis of pancreatic cancer and/or the expansion of already disseminated micrometastases.
Pancreatic cancer is also characterized by having an extensive stromal component. It is hypothesized that this bulk of fibroid tissue may be one of the reasons pancreatic cancer remains particularly insensitive to chemotherapeutic agents. Another arm of our research attempts to investigate whether tumor fibroblasts, like vascular endothelial cells, are responsive to CXC-CXCR crosstalk signaling triggered initially by epithelial K-Ras activation.
It is well established that mutational activation of K-Ras occurs very early in pancreatic ductal dysplasia and remains an important signaling impetus through the development of malignancy. We are investigating whether the signaling crosstalk between Ras and CXC chemokines is similarly triggered early in cancer progression by screening patient samples of initial dysplasia (pancreatic intraepithelial neoplasia, PanIN) to frank adenocarcinoma. By understanding the progression this signaling, we hope to uncover biomarkers to be used for screening and earlier detection.
Our research revolves around understanding how the Ras family of small GTPases impinges upon tumor invasion and metastasis, specifically in pancreatic ductal cancer. Ras is a nodal point of signaling, with input and activation from a wide range of stimuli including receptor tyrosine kinases, G protein-coupled receptors, integrins and extracellular matrix interactions, and chemokines. Once activated, Ras in turn triggers several signaling cascades that lead to a variety of transformed phenotypes including loss of cell cycle control, decreased cell death, and metastatic spread. Of particular interest to my lab is delineating how Ras activation in epithelial tumor cells drives signaling crosstalk to other compartments of the tumor microenvironment including stromal fibroblasts, macrophages, and vascular components. Paracrine signaling among these disparate cell populations likely contributes to protection of epithelial cells from cell cycle arrest, apoptosis, and senescence, as well as facilitating dedifferentiation and a hallmark of tumor progression and metastasis, epithelial-mesenchymal transition (EMT).
At the same time that crosstalk affects the epithelial cells, there is evidence that aberrant activation of Ras leads to changes in extracellular matrix (ECM). Reorganization and dissolution of ECM by proteases and other enzymes accelerates cell migration for locoregional invasion and distal metastasis. In addition to Ras effects on the ECM architecture, we have recently shown that activation of this family of GTPases in pancreatic cancer leads to expression and secretion of CXC chemokines that is in part MAP kinase-dependent. Vascular endothelial cells are sensitive to these chemokines via CXCR2 receptors, and respond by showing increased migration, invasion, and organization into vessel precursors. This angiogenesis may provide not only a means to nourish nascent tumors, but also serve as a conduit for malignant spread. As a result, we are interested in testing the hypothesis that small molecule inhibitors of the CXC-CXCR signaling axis may reduce the invasion and metastasis of pancreatic cancer and/or the expansion of already disseminated micrometastases.
Pancreatic cancer is also characterized by having an extensive stromal component. It is hypothesized that this bulk of fibroid tissue may be one of the reasons pancreatic cancer remains particularly insensitive to chemotherapeutic agents. Another arm of our research attempts to investigate whether tumor fibroblasts, like vascular endothelial cells, are responsive to CXC-CXCR crosstalk signaling triggered initially by epithelial K-Ras activation. It is well established that mutational activation of K-Ras occurs very early in pancreatic ductal dysplasia and remains an important signaling impetus through the development of malignancy. We are investigating whether the signaling crosstalk between Ras and CXC chemokines is similarly triggered early in cancer progression by screening patient samples of initial dysplasia (pancreatic intraepithelial neoplasia, PanIN) to frank adenocarcinoma. By understanding the progression this signaling, we hope to uncover biomarkers to be used for screening and earlier detection.
Finally, some of our recent work has demonstrated an interaction between K-Ras and the RNA-binding protein, HuR. Current investigations are looking at how K-Ras activation via genetic mutation influences HuR function and regulation of the cancer progression transcriptome, and in turn, how HuR governs K-Ras-dependent signaling in tumor epithelial cells.
A. Thadi, W.F. Morano, M. Khalili, B.B. Babcock, M.F. Shaikh, D.S. Foster, Y. Piazza, E.M. Gleeson, E. Goldstein, L. Steele, P.M. Campbell, B. Lin, M.R. Pincus, W.B. Bowne. 2021. Molecular targeting of H/MDM-2 oncoprotein in human colon cancer cells and stem-like colonic epithelial derived progenitor cells. Anticancer Res, 41:27-42. Pubmed.
Sliker B.H. and Campbell P.M. 2020. Ras and Ras Signaling as a therapeutic target in cancer. In Comprehensive Pharmacology, Terry Kenakin, Ph.D., editor, in press.
A. Thadi, E.M. Gleeson, M. Khalili, M.F. Shaikh, E. Goldstein, W.F. Morano, L.M. Daniels, N. Grandhi, H. Glatthorn, S.D. Richard, P.M. Campbell, M.R. Pincus, W.B. Bowne. 2020. Anti-cancer tumor cell necrosis of multidrug resistant ovarian cancer cell lines depends on high expression of HDM-2 protein in their membranes. Ann Clin Lab Sci, 50:611-624. Pubmed
A. Thadi, L. Lewis, E. Goldstein, A. Aggarwal, M. Khalili, L. Steele, B. Polyak, S. Seydafkan, M.H. Bluth, K.A. Ward, M. Styler, P.M. Campbell, M.R. Pincus, W.B. Bowne. 2020. Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells but Not Normal Hematopoietic Cells. Anticancer Res, 40:4857-4867. Pubmed
M.C. Stout and P.M. Campbell. 2018. RASpecting the oncogene: New pathways to therapeutic advances. Biochem Pharm, 158: 217-228. Pubmed
M.C. Stout, S. Narayan, E.S. Pillet, J.S. Salvino, P.M. Campbell. 2018. Inhibition of CX3CR1 Reduces Cell Motility and Viability in Pancreatic Adenocarcinoma Epithelial Cells. Biochem Biophys Res Commun, 495:2264– 2269. PubMed
S. Lal*, E. Cheung*, M. Zarei*, R. Preet, S.N. Chand, N.C. Mambelli-Lisboa, C. Romeo, M.C. Stout, E. Londin, A. Goetz, C. Yabar, A. Nevler, C.J. Yeo, P.M. Campbell, J.M. Winter, D.A. Dixon, J.R. Brody. 2017. CRISPR knockout of the HuR gene in pancreatic and colorectal cancer cells causes a xenograft lethal phenotype. * Contributed equally. Mol Cancer Res, 15:696-707. PubMed
M.C. Stout, E. Asiimwe, J.R. Birkenstamm, S.Y. Kim, P.M. Campbell. 2014. Analyzing Ras-associated Cell Proliferation Signaling. Methods Mol Biol, 1170:393-409. PubMed
P.M. Campbell. 2014. Oncogenic Ras pushes (and pulls) cell cycle progression through ERK activation. Methods Mol Biol, 1170:155-163. PubMed
H.R. Siddique, D.J. Liao, S.K. Mishra, T. Schuster, L. Wang, B. Matter, P.M. Campbell, P. Villalta, S. Nanda, Y. Deng, M. Saleem. 2012. Epicatechin-rich cocoa polyphenol inhibits Kras-activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model. Int J Cancer, 131:1720–1731. PubMed
J.J. Yeh, J.P. Madigan, P.M. Campbell, P.J. Roberts, L.M. DeGraffrenreid, C.J. Der. 2011. Targeting Ras for anti-cancer drug discovery. In Intercellular Signaling in Development and Disease, E.A. Dennis and R.A. Bradshaw, eds. Elsevier Press, pp. 335-355.
P.M. Campbell*, N. Boufaied*, J.J. Fiordalisi, A.D. Cox, P. Falardeau, C.J. Der, H. Gourdeau. 2010. TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-MAPK signaling. J Mol Signal, 5:18. * Contributed equally PubMed
Y. Matsuo*, P.M. Campbell*, R.A. Brekken, B. Sung, M.M. Ouellette, J.B. Fleming, B.B. Aggarwal, C.J. Der, S. Guha. 2009. K-Ras promotes angiogenesis mediated by immortalized human pancreatic epithelial cells through MAP kinase signaling pathways. Mol Cancer Res, 7:799-808. * Contributed equally. PubMed
P.M. Campbell, K.M. Lee, M.M. Ouellette, H.J. Kim, A.L. Groehler, V. Khazak, C.J. Der. 2008. Ras-driven transformation of human nestin-positive pancreatic epithelial cells. Methods Enzymol 439:451-65. PubMed
P.M. Campbell, A.L. Groehler, K.M. Lee, M.M. Ouellette, V. Khazak, C.J. Der. 2007. K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by Raf and phosphatidylinositol 3-kinase signaling. Cancer Res 67:2098-2106. PubMed
This Fox Chase professor participates in the Undergraduate Summer Research Fellowship.
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