For good reason, much of modern cancer research has focused on genes whose products regulate cell growth and survival. However, it is becoming increasingly clear that genes whose products regulate tissue architecture play a critical role in tumour progression. In my laboratory we are determining how the functions of such genes are co-opted during breast and ovarian carcinoma progression.

Breast and ovarian carcinomas both arise in 'epithelia'. Architecturally, the epithelial tissues affected are made up of tightly linked cells that line ducts (ie. breast) or surfaces (ie. ovary). The links between epithelial cells are initiated and maintained by cell adhesion molecules (ie. cadherins). We have developed specialized, 3-dimensional models that allow us to recapitulate normal epithelial tissue architecture outside the body in a tissue culture dish. We are now modulating the expression and function of cell adhesion molecules in these cultures to determine how architectural disruption allows epithelial cells to break away from the original tumor and begin invading surrounding tissues.

Tumor cell invasion is a prerequisite for metastasis. For invasion to occur, cells that have been released from the original tumor mass must be able to migrate through the extracellular matrix (ECM) which acts as a scaffold between and within tissues. Specialized adhesion molecules that link cells to the ECM (ie. integrins) generate signals within cells that cause them to either remain stationary or become migratory. We are determining the specific molecules that are involved in regulating this migratory switch in breast and ovarian tumor cells.

McHardy LM, Warabi K, Andersen RJ, Roskelley CD & Roberge M. Strongylophorine-26, a Rho-dependent inhibitor of tumor cell invasion that reduces actin stress fibers and induces non-polarized lamellipodial extensions. Mol. Cancer Therapeutics 4:772-778, 2005.

Kelley TW, Huntsman D, McNagny KM, Roskelley CD & Hsi ED. Podocalyxin: a marker of blasts in acute leukemia. Am. J. Clin. Pathol. 124:1-9, 2005.

Filipenko NR, Attwell S, Roskelley CD & Dedhar S. Integrin-linked kinase activity regulates Rac and Cdc42-mediated actin cytoskeleton reorganization via alpha-pix. Oncogene 24:5837, 2005.

Williams DE, Austin P, Marrero ARD, Van Soest RV, Matainaho T, Roskelley CD, Roberge M, & Andersen RJ. Neopetrosiamides, peptides from the marine sponge Neopetrosia sp. that inhibit amoeboid invasion by human tumor cells. Organic Letters 7:4173, 2005.

Wong AS, Roskelley CD, Pelech S, Miller D, Leung PC & Auersperg N. Progressive changes in Met-dependent signaling in a human ovarian surface epithelial model of malignant transformation. Exp. Cell Res. 299:248, 2004.

Somasiri A, Nielson J, Makretsov N, McCoy ML, Gilks CB, Huntsman D, Gelmon KA, Kershaw DB, McNagny KM & Roskelley CD. The Anti-adhesin Podocalyxin is an independent predictor of breast cancer progression. Cancer Research 64:5068, 2004.

Ward KR, Zhang KX, Somasiri AM, Roskelley CD & Schrader JW. Expression of activated M-Ras in a murine mammary epithelial cell line induces epithelialmesenchymal transition and tumorigenesis. Oncogene 23:1187-96, 2004.

McHardy LM, Sinotte R, Troussard A, Sheldon C, Church J, Williams DE, Andersen RJ, Dedhar S, Roberge M & Roskelley CD. The tumor invasion inhibitor dihydromotuporamine C activates RHO, remodels stress fibers and focal adhesions, and stimulates sodium-proton exchange. Cancer Res. 15:1468-74, 2004.

Warabi K, McHardy LM, Matainaho L, Van Soest RV, Roskelley CD, Roberge M & Andersen RJ. Stronglyophorine-12, a new meroditerpenoid isolated from the marine sponge Petrosia cortacta that exhibits anti-invasion activity. J. Natural Products 27:1387, 2004.

Maines-Bandiera SL, Huntsman D, Lestou VS, Kuo WL, Leug PC, Horsman RD, Wong As, Woo MM, Choi KK, Roskelley CD & Auersperg N. Epitheliomesenchymal transition in a neoplastic ovarian epithelial hybrid cell line. Differentiation 72:150-61, 2004.

Somasiri A., Howarth A., Goswami D., Dedhar S and Roskelley C.D. (2001) Overexpression of the integrin-linked kinase mesenchymally transforms mammary epithelial cells. J. Cell Sci., 114(6):1125-36.

Somasiri AM, Wu C, Ellchuk T, Turley S, and Roskelley CD (2000) Phosphoinositide 3-OH kinase is required for adherens junction-dependent mammary epithelial cell spheroid formation. Differentiation, 66:116-125.

Troussard A.A., Costello P., Yoganatha T.N., Kumagai S., Roskelley C.D. and Dedhar S. (2000) The integrin-linked kinase induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of MMP-9. Oncogene, 19:5444-5452.

Attwell S, Roskelley CD and Dedhar S (2000) The integrin-linked kinase (ILK) suppressess anoikis. Oncogene, 19:3811-3815.

Ong A, Maines-Bandiera S, Roskelley CD and Auersperg N (2000) An ovarian epithelial adenocarcinoma line derived from SV40/E-cadherin transfected normal human ovarian surface epithelium. Int. J. Cancer. 85:430-437.

Auersperg N, Pan J, Grove BD, Peterson T, Fisher J, Maines-Bandiera S, Somasiri A and Roskelley CD (1999) E-Cadherin induces mesenchymal-to-epithelial transition in the human ovarian surface epithelium. PNAS (USA). 96: 6249-6254.

Roskelley CD, Wu C and Somasiri A (1999) Analysis of mammary gland morphogenesis. Mets. in Mol. Biol., 136:23-37.

Somasiri A and Roskelley CD (1999) Cell shape and integrin signaling regulate the differentiation state of mammary epithelial cells. Mets. in Mol. Biol., 129:271-284.

Muschler J, Lochter A, Roskelley CD, Yurchenco P and Bissell MJ (1999) Division of labour among integrins and an E3 laminin receptor to signal morphogenesis and §-casein expression in mammary epithelial cells. Mol. Biol. Cell., 10:2817-2828.

Wong AST, Maines-Bandiera SL, Rosen B, Wheelock MJ, Leung PCK, Roskelley CD and Auersperg N (1999) Constitutive and conditional cadherin expression in human ovarian surface epithelium: influence of family histories of ovarian cancer. Int. J. Cancer. 81: 180-188.

Novak A, Hsu SC, Leung-Hagesteijn C, Radeva G, Papkoff J, Montesano R, Roskelley CD, Grosschedl R and Dedhar S (1998) Cell Adhesion and the integrin-linked kinase (ILK) regulate the LEF-1 and §-catenin signalling pathways. PNAS (USA) 95:4374-4379.

Myers CM, Schmidhauser C, Mellentin J, Fragoso G, Roskelley CD, Casperson G, Mossi R, Pujuguet P, Hager G and Bissell MJ (1998) Characterization of BCE-1: a transcriptional enhancer regulated by prolactin and extracellular matrix and modulated by the state of histone acetylation. Mol. Cell Biol. 18:2184-2195.

Research Associates:   Lixin Zhou

Technician:   Pamela Austin