In normal tissue, the stroma provides an inhibitory barrier to restrict epithelial cell growth. While this barrier function remains in early tumor development, it can be reversed during later stages of tumorigenesis, and the stroma subverted or """"""""activated"""""""" to participate in tumor development. How this process occurs is not known, but is thought to involve changes in the stromal fibroblasts, the predominant cell type in the stroma, which produce and modify the stromal extracellular matrix (ECM). One reason that we know so little about stromal activation is that we lack a suitable physiologic experimental system. To that end, we have developed a novel in vivo-like 3D stromal system derived from fibroblasts at progressive stages of cancer development. In initial comparisons of normal and tumor-associated stroma, we have observed structural and biochemical alterations in both fibroblasts and their secreted ECMs. Based on these preliminary data, we hypothesize that altered attachment signaling within the activated stromal fibroblasts contributes to the tumor promoting properties of the tumor-associated stroma. We also propose that inhibiting these signals can block cancer progression by restoring the tumor-repressive property of normal stroma. To test these hypotheses, we propose 2 aims.
Aim 1 will test the hypothesis that alterations in the integrin-dependent Src and FAK signaling pathway are critical to the development of tumor-promoting stroma.
Aim 2 will test the hypothesis that epithelial tumor-cell invasion can be repressed by targeting the fundamental stromagenic signaling pathways. The completion of the proposed studies should assist us to better understand the process of stromal activation, and provide insights into how to manipulate the process to contain epithelial tumor transformation or cause tumor regression. Ultimately, our long-term goal is to target the tumor-associated stroma thus maintaining cancer as an innocuous chronic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA113451-05
Application #
7813969
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2006-07-01
Project End
2012-04-11
Budget Start
2010-06-01
Budget End
2012-04-11
Support Year
5
Fiscal Year
2010
Total Cost
$240,604
Indirect Cost
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Roy, Ishan; Boyle, Kathleen A; Vonderhaar, Emily P et al. (2017) Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma. Lab Invest 97:302-317
Franco-Barraza, Janusz; Beacham, Dorothy A; Amatangelo, Michael D et al. (2016) Preparation of Extracellular Matrices Produced by Cultured and Primary Fibroblasts. Curr Protoc Cell Biol 71:10.9.1-10.9.34
Alexander, Jennifer; Cukierman, Edna (2016) Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions. Curr Opin Cell Biol 42:80-93
Malik, Ruchi; Lelkes, Peter I; Cukierman, Edna (2015) Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol 33:230-6
Bassi, Daniel E; Cenna, Jonathan; Zhang, Jirong et al. (2015) Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6). Mol Carcinog 54:1122-31
Cao, Xuan; Lin, Yuan; Driscoll, Tristian P et al. (2015) A Chemomechanical Model of Matrix and Nuclear Rigidity Regulation of Focal Adhesion Size. Biophys J 109:1807-17
Rybinski, Brad; Franco-Barraza, Janusz; Cukierman, Edna (2014) The wound healing, chronic fibrosis, and cancer progression triad. Physiol Genomics 46:223-44
Håkanson, Maria; Cukierman, Edna; Charnley, Mirren (2014) Miniaturized pre-clinical cancer models as research and diagnostic tools. Adv Drug Deliv Rev 69-70:52-66
Campbell, Catherine B; Cukierman, Edna; Artym, Vira V (2014) 3-D extracellular matrix from sectioned human tissues. Curr Protoc Cell Biol 62:Unit 19.16.1-20
Chang, Yu-Chung; Zhang, Hao; Franco-Barraza, Janusz et al. (2014) Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling. Structure 22:1810-1820

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