For most cancers, the cause of patient death is either local
invasion into critical areas or metastasis - dissemination of tumor cells from
the primary tumor to many parts of the body followed by formation of new tumors
at those distant sites. By understanding
the mechanisms by which tumor cells invade and metastasize, we will have better
chances of developing appropriate therapies.
Tumor cell motility and the orientation of tumor cells by chemotaxis
make important contributions to invasion and metastasis.
Three types of
cancer are being studied. Glioblastoma
and head and neck cancer invade locally into critical areas and the primary
tumors are not fully removable by surgery.
Breast cancer, although the primary tumor can be fully removed,
metastasizes to distant sites, and the resulting metastases can lead to poor
prognosis. Tissue culture studies of invasion
and signaling of these cancers are combined with in vivo analysis in mice.
Two types of in vivo
approaches being used for studying invasion and metastasis: 1) injection of
tumor cells into the orthotopic site (brain, floor of mouth, or mammary fat pad
for glioma, head and neck cancer, and breast cancer respectively), and 2)
formation of tumors in transgenic mice using oncogenes. The injection assays allow the rapid
molecular manipulation of cell lines to identify important signaling pathways
that contribute to metastasis. The
transgenic mouse system provides a more clinically relevant model in which
tumors develop from the appropriate tissue directly.
The lab has also studied Dictyostelium discoideum and Saccharomyces cerevisiae. Dictyostelium and Saccharomyces provide a molecular/genetic dissection of chemotaxis. Both utilize G protein-coupled signal transduction pathways to mediate orientation responses. The movies sections demonstrate examples of these valuable model systems for studies of chemotaxis and directed cell responses.
Zhou ZN, Sharma VP, Beaty BT, Roh-Johnson M, Peterson EA, Van Rooijen N, Kenny PA, Wiley HS, Condeelis JS, Segall JE. Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo. Oncogene. 2014 Jul 17;33(29):3784-93.
Entenberg D, Kedrin D, Wyckoff J, Sahai E, Condeelis J, Segall JE. Imaging tumor cell movement in vivo. Curr Protoc Cell Biol. 2013 Mar;Chapter 19:Unit19.7.
Friedl P, Locker J, Sahai E, Segall JE. Classifying collective cancer cell invasion. Nat Cell Biol. 2012 Aug;14(8):777-83.
Hulit J, Kedrin D, Gligorijevic B, Entenberg D, Wyckoff J, Condeelis J, Segall JE. The use of fluorescent proteins for intravital imaging of cancer cell invasion. Methods Mol Biol. 2012;872:15-30.
Kim RS, Avivar-Valderas A, Estrada Y, Bragado P, Sosa MS, Aguirre-Ghiso JA, Segall JE. Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. PLoS One. 2012;7(4):e35569. 12:143-52.
Boimel PJ, Smirnova T, Zhou ZN, Wyckoff J, Park H, Coniglio SJ, Qian BZ, Stanley ER, Cox D, Pollard JW, Muller WJ, Condeelis J, Segall JE. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res. 2012 Feb 7;14(1):R23
Coniglio SJ, Eugenin E, Dobrenis K, Stanley ER, West BL, Symons MH, Segall JE. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med. 2012 May 9;18:519-27.
Harris T, Jimenez L, Kawachi N, Fan JB, Chen J, Belbin T, Ramnauth A, Loudig O, Keller CE, Smith R, Prystowsky MB, Schlecht NF, Segall JE, Childs G. 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. 2012 Mar;180(3):917-28.
Hernandez L, Magalhaes MA, Coniglio SJ, Condeelis JS, Segall JE. Opposing roles of CXCR4 and CXCR7 in breast cancer metastasis. Breast Cancer Res. 2011;13(6):R128.
Zhou ZN, Boimel PJ, Segall JE. Tumor-stroma: In vivo assays and intravital imaging to study cell migration and metastasis. Drug Discov Today Dis Models. 2011 Fall;8(2-3):95-112.
Smirnova T, Zhou ZN, Flinn RJ, Wyckoff J, Boimel PJ, Pozzuto M, Coniglio SJ, Backer JM, Bresnick AR, Condeelis JS, Hynes NE, Segall JE. Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis. Oncogene. 2012 Feb 9;31(6):706-15.
Boimel PJ, Cruz C, Segall JE. A functional in vivo screen for regulators of tumor progression identifies HOXB2 as a regulator of tumor growth in breast cancer. Genomics. 2011 Sep;98(3):164-72.
Smirnova T, Adomako A, Locker J, Van Rooijen N, Prystowsky MB, Segall JE. In vivo invasion of head and neck squamous cell carcinoma cells does not require macrophages. Am J Pathol. 2011 Jun;178(6):2857-65.
Piatkevich KD, Hulit J, Subach OM, Wu B, Abdulla A, Segall JE, Verkhusha VV. Monomeric red fluorescent proteins with a large Stokes shift. Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5369-74.
Hernandez L, Smirnova T, Wyckoff J, Condeelis J, Segall JE. In vivo assay for tumor cell invasion. Methods Mol Biol. 2009;571:227-38.