Abstract 4306: Lack of TGF-β signaling induces a switch from single to collective cell migration in vivo

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.4306-4306
• Main Authors: Matise, Lauren A., Palmer, Trenis D., Ashby, William J., Nashabi, Abudi, Chytil, Anna, Aakre, Mary, Gorska, Agnieszka, Pickup, Michael W., Zijlstra, Andries, Moses, Harold L.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-4306

Transforming growth factor-beta (TGF-β) has a dual role during tumorigenesis initially as a suppressor and then as a promoter. In stromal fibroblasts, TGF-β signaling suppresses tumorigenesis in adjacent epithelia, while its ablation potentiates tumor formation. Concurrently, epithelial TGF-β signaling regulates fibroblast recruitment and activation. Yet, the role of TGF-β in stromal-epithelial migration during tumorigenesis is unknown. We hypothesize that TGF-β is a critical regulator of tumor-stromal interactions that promote mammary tumor cell migration and invasion. We are using the chicken embryo chorioallantoic membrane (CAM) model to study this interplay by grafting both breast cancer epithelial cells, isolated from either TGF-β receptor II knockout (TβRII-deficient) or TβRII floxed (control) mice, and fibroblasts onto the CAM. Intravital microscopy revealed fibroblast stimulation of either a single cell/strand migration of control cells or collective migration of TβRII-deficient cells, both along the vasculature. Epithelial clusters at the epithelial-stromal boundaries of TβRII-deficient tumors express E-cadherin, p120, and β-catenin, while control epithelia in these regions express αSMA. TβRII-deficient tumors also exhibit a two-fold greater local CAM metastasis than control tumors. Epithelial tumor RNA isolated by laser capture microdissection was analyzed on a qPCR array. In TβRII-deficient epithelium compared to control epithelium, we found upregulation of Igfbp4 and Tspan13 and downregulation of Col1α2, Bmp7, Wnt11, Gng11, Vcan, Tmeff1, and Dsc2. Western and qPCR analyses validated these targets in vitro. For current and future studies determining the relevance of these targets to migration patterning, we achieved Wnt11 overexpression in TβRII-deficient cells, as well as knockdown of Wnt11 and Tmeff1 in control cells. Our findings about TGF-β signaling in stromal-epithelial interactions are important in identifying migratory mechanisms that can be targeted as recourse for breast cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4306. doi:1538-7445.AM2012-4306