General area of research: Signaling mechanisms between bone and cancer cells that promote metastasis, with current focus on prostate cancer.
The major cause of mortality from prostate cancer is metastatic disease for which there is currently no effective cure. For reasons that remain incompletely understood, bone is the most common site for prostate cancer metastasis. Reciprocal signaling between invading prostate cancer cells and host bone cells is central to metastatic tumor development. Understanding these cell-cell interactions will lead to effective diagnostic and therapeutic strategies to prevent/arrest metastatic spread of prostate carcinoma.
My current research stems from the hypothesis that prostate cancer cells and bone cells interact via the hedgehog signaling pathway to promote bone metastasis. Sonic hedgehog (Shh) is a member of the hedgehog family of ligands that activate an intracellular signaling cascade upon binding to transmembrane receptors (Patched) leading to transcriptional regulation of specific target genes by the Gli family of transcription factors. Our previous work has demonstrated that Shh-expressing epithelial cells and Gli-expressing mesenchymal cells in embryonic mouse prostate interact via the Shh-Gli pathway to promote cell proliferation and ductal morphogenesis. We have also shown that the genes for Shh and Gli are expressed in human prostate cancer, and that Shh-expressing prostate cancer cells and Gli-expressing stroma collaborate to promote prostate tumor growth in a mouse xenograft model. Our present research extends these observations and investigates signaling interactions via the Shh-Gli pathway between prostate cancer cells and bone cells to promote prostate carcinoma metastasis, using both in vitro and in vivo models.
Lamm, Marilyn and Bushman, Wade (2005). Hedgehog Signalling in Prostate Morphogenesis in Howie, Sarah and Fisher, Carolyn, Shh and Gli Signalling and Development. Landes Bioscience.
Fan L, Pepicelli CV, Dibble CC, Catbagan W, Zarycki JL, Laciak R, Gipp J, Shaw A, Lamm MLG, Munoz A, Lipinski R, Thrasher JB, Bushman W (2004). Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology: 145, 3961-3970.
Walterhouse DO, Lamm MLG, Villavicencio E, Iannaccone P (2003). Emerging roles for hedgehog-Patched-Gli signal transduction in reproduction. Biology of Reproduction : 69, 8-14.
Lamm MLG, Catbagan WS, Laciak RJ, Barnett DH, Hebner CM, Gaffield W, Walterhouse D, Iannaccone P, Bushman W (2002). Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Developmental Biology : 249, 349-366.
Lamm MLG, Podlasek CA, Barnett DH, Lee J, Clemens JQ, Hebner CM, Bushman W (2001). Mesenchymal factor bone morphogenetic protein 4 restricts ductal budding and branching morphogenesis in the developing prostate. Developmental Biology : 232, 301-314.