The objective of this application is to examine the contributions of the EGF receptor family members ErbB1 and ErbB2/ErbB3 in vivo motility, tumor cell intravasation and metastasis. A better understanding of how tumor cells enter blood vessels will enhance our ability to develop therapies and diagnostic tests for improving treatment of patients with cancer. We have found in the previous cycle that increased ErbB1 or ErbB2/ErbB3 signaling can enhance tumor cell intravasation and metastasis, without affecting in vivo growth rates. We hypothesize that the increased chemotactic responses that we observe in vitro and increased invasive responses observed in vivo enable metastatic tumor cells to detect leaky vessels and move towards them, resulting in enhanced intravasation.
In Specific Aim 1, we perform an analysis of the C terminal tyrosines on ErbB2 and ErbB3 that are required for enhancement of intravasation and metastasis.
In Specific Aim 2, we use multiphoton microscopy imaging to evaluate tumor cell migration in the primary tumor relative to blood vessels and test the roles of ErbBs and vessel leakiness in directly stimulating tumor cell motility.
In Specific Aim 3, we test whether external gradients of ligand are required for enhancement of tumor cell motility, intravasation and metastasis. This proposal makes use of orthotopic, in vivo models of spontaneous metastasis together with intravital imaging of primary tumors to perform unique measurements of the contributions of ErbBs on intravasation and metastasis.
|Jimenez, Lizandra; Lim, Jihyeon; Burd, Berta et al. (2017) miR-375 Regulates Invasion-Related Proteins Vimentin and L-Plastin. Am J Pathol 187:1523-1536|
|Jimenez, Lizandra; Sharma, Ved P; Condeelis, John et al. (2015) MicroRNA-375 Suppresses Extracellular Matrix Degradation and Invadopodial Activity in Head and Neck Squamous Cell Carcinoma. Arch Pathol Lab Med 139:1349-61|
|Zhou, Z N; Sharma, V P; Beaty, B T et al. (2014) Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo. Oncogene 33:3784-93|
|Hulit, James; Kedrin, Dmitriy; Gligorijevic, Bojana et al. (2012) The use of fluorescent proteins for intravital imaging of cancer cell invasion. Methods Mol Biol 872:15-30|
|Harris, Thomas; Jimenez, Lizandra; Kawachi, Nicole et al. (2012) Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Am J Pathol 180:917-28|
|Smirnova, T; Zhou, Z N; Flinn, R J et al. (2012) Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis. Oncogene 31:706-15|
|Kim, Ryung S; Avivar-Valderas, Alvaro; Estrada, Yeriel et al. (2012) Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. PLoS One 7:e35569|
|Boimel, Pamela J; Cruz, Cristian; Segall, Jeffrey E (2011) A functional in vivo screen for regulators of tumor progression identifies HOXB2 as a regulator of tumor growth in breast cancer. Genomics 98:164-72|
|Locker, Joseph; Segall, Jeffrey E (2011) Breast cancer: the matrix is the message. Am J Pathol 178:966-8|
|Roussos, Evanthia T; Balsamo, Michele; Alford, Shannon K et al. (2011) Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. J Cell Sci 124:2120-31|
Showing the most recent 10 out of 25 publications