The overall objective of this proposal is to provide a training vehicle that will allow the applicant to be prepared for a successful career as an independent investigator in biomedical research. This research is focused on understanding mechanisms that promote tumor cell immobility with the notion that the promotion of immobility inhibits metastatic dissemination and subsequent colonization. We hypothesize that tumor cell metastasis is dependent upon the dysregulation of factors associated with adhesion and that inhibition of metastasis can be achieved by targeting factors that can promote adhesion and immobility. We will test this hypothesis using the following specific aims:
Aim 1 : Analyze functional migration deficiency of the low metastatic variant of the human epidermoid cell line HEp3. Using quantitative analysis of metastasis we will determine what aspect of the metastatic cascade is deficient in HEp3 M-. Furthermore, we will utilize intravital imaging to determine if in vivo migration is altered in these cells and impacted by p38 activity.
Aim 2 : Determine the importance of CD166 and a3p1 integrin in promoting tumor cell immobility. We have identified both a3p1 and CD166 are cell adhesion molecule associated with CD151 mediated immobility. For each of these molecules we will alter the expression by shRNA or transgene expression and disrupt the molecular function using blocking peptides or genetic alterations in order to determine the importance of their interaction with CD151 in promoting tumor cell immobility.
Aim 3 : Using intravital imaging we will identify genes that are able to prevent metastasis by promoting tumor cell immobilization. Using quantitative analysis of metastasis in mouse and chick xenograft, models, genes capable of promoting tumor cell immobility will be further investigated for their ability to intervene in tumor growth, intravastation, arrest, and distant organ colonization.
The movement of tumor cells from the original tumor to distant organs is responsible for the lethal aspects associated with the progression of cancer. Techniques to treat and control the tumor's progression routinely involve surgical removal. However, this intervention is no longer curative if tumor cells have disseminated to other organs and begun to form secondary colonies. This one fact makes it necessary to understand the factors involved in migration and pursue mechanisms that promote tumor cell immobility and thereby, inhibit metastasis.
|Palmer, Trenis D; Martínez, Carlos H; Vasquez, Catalina et al. (2014) Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression. Cancer Res 74:173-87|
|Hansen, Amanda G; Arnold, Shanna A; Jiang, Ming et al. (2014) ALCAM/CD166 is a TGF-?-responsive marker and functional regulator of prostate cancer metastasis to bone. Cancer Res 74:1404-15|
|Hansen, Amanda G; Freeman, Tanner J; Arnold, Shanna A et al. (2013) Elevated ALCAM shedding in colorectal cancer correlates with poor patient outcome. Cancer Res 73:2955-64|