Integrins and growth factor receptors function in a cooperative manner to regulate cellular behavior. During the previous funding cycle, we have begun to explore a signaling module in pancreatic carcinoma cells that appears to regulate the metastatic properties of these cells. We found that epidermal growth factor receptor (EGFR) together with the integrin avb5 promotes Src kinase signaling that appears to directly regulate the invasive properties of both human and murine pancreatic tumor cells. We have identified two pathways of tumor cell migration in vitro that can be distinguished by their differential dependence on Src kinase activity. Cell migration on fibronectin, collagen, and laminin mediated by b1 integrins is independent of Src, while migration on vitronectin mediated by integrin avb5 depends on Src. In Preliminary Results, we show that the EGFR/Src/avb5 signaling module initiates a cascade leading to tumor cell invasion in both orthotopic and spontaneous pancreatic cancer cell metastasis models in vivo. We have selected matched primary and metastatic pancreatic cell lines, and found that activation or overexpression of EGFR together with ligation of integrin avb5 appears to induce Src activity and downstream signaling leading to increased invasive behavior of these cells. We find that pancreatic cancer cells expressing increased Src kinase activity invade from the primary tumor deep into the host stroma while primary tumors with minimal Src activity remain confined within the tumor parenchyma as measured by intravital multi-photon imaging. In this proposal, we will characterize the mechanism by which EGFR/Src/avb5 signaling promotes invasion and metastasis. We will explore how Src tyrosine phosphorylation of specific substrates influences this invasive behavior. These studies will focus on how Src not only activates the cell migration machinery, but how it promotes the uncoupling of tumor cell adherens junctions. Finally we will explore how pharmacological and/or genetic disruption of this EGFR/avb5/Src signaling module on metastatic pancreatic cancer cells reverses their metastatic phenotype in vivo. In this case, we will evaluate the possible therapeutic relevance of these targets in orthotopic pancreatic cancer models, as well as a genetic model of spontaneous primary and metastatic pancreatic cancer. These studies should provide molecular insight into a signaling cascade that appears to contribute to the invasive behavior of pancreatic carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045726-24
Application #
7826800
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
1988-04-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
24
Fiscal Year
2010
Total Cost
$361,229
Indirect Cost
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Seguin, Laetitia; Camargo, Maria F; Wettersten, Hiromi I et al. (2017) Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers. Cancer Discov 7:1464-1479
Cosset, Érika; Ilmjärv, Sten; Dutoit, Valérie et al. (2017) Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma. Cancer Cell 32:856-868.e5
Seguin, Laetitia; Desgrosellier, Jay S; Weis, Sara M et al. (2015) Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol 25:234-40
Franovic, Aleksandra; Elliott, Kathryn C; Seguin, Laetitia et al. (2015) Glioblastomas require integrin ?v?3/PAK4 signaling to escape senescence. Cancer Res 75:4466-73
Desgrosellier, Jay S; Lesperance, Jacqueline; Seguin, Laetitia et al. (2014) Integrin ?v?3 drives slug activation and stemness in the pregnant and neoplastic mammary gland. Dev Cell 30:295-308
Seguin, Laetitia; Kato, Shumei; Franovic, Aleksandra et al. (2014) An integrin ??-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol 16:457-68
Seguin, Laetitia; Gozo, Maricel; Weis, Sara M et al. (2014) Targeting the Achilles' heel of drug-resistant cancer stem cells. Cell Cycle 13:2017-8
Lau, Steven K M; Shields, David J; Murphy, Eric A et al. (2012) EGFR-mediated carcinoma cell metastasis mediated by integrin ?v?5 depends on activation of c-Src and cleavage of MUC1. PLoS One 7:e36753
Huang, M; Anand, S; Murphy, E A et al. (2012) EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation. Oncogene 31:2783-93
Jaquish, Dawn V; Yu, Peter T; Shields, David J et al. (2011) IGF1-R signals through the RON receptor to mediate pancreatic cancer cell migration. Carcinogenesis 32:1151-6

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