Antoine Karnoub Lab
Mechanistic studies of cancer pathogenesis have portrayed cancer as a cell-autonomous phenomenon, in which the behavior of tumors can be understood in terms of the mutant genes that cancer cells carry in their genomes. This view implies that the behavior of a tumor mass can be understood only by studying the intrinsic traits of its neo- plastic cells. However, in the case of breast carcinomas, the neoplastic epithelial cells within the tumor mass co-exist with a variety of stromal mesenchymal cell types which form as much as 80% of the tumor mass. This mesenchymal bed is integral for tumor growth as it controls the survival of neoplastic cells and the overall dynamics of tumor progression. Therefore, defining the nature of the signals exchanged between the stromal niche and the cancer cells will provide new insights into how breast cancers develop and metastasize.
My research program in the next few years will focus on how the tumor microenvironment influences tumor progression. Specifically, my laboratory will pursue three major questions: First, where does the cancer-associated stroma come from and how are stromal cells recruited into primary tumors? Second, what is the nature of the heterotypic interactions operating between the stromal and the epithelial compartments within primary tumors, and how do these interactions facilitate cancer development? Third, what roles does the stroma of the secondary tissue play in enabling disseminated cancer cells to colonize those tissues?
1) Recruitment of stromal cells: The stroma within breast carcinomas might derive from local tissues adjacent to the tumor site. However, increasing evidence suggests that the tumor stroma derives from distant sources within the body, such as the bone marrow. My recent research indicated that developing tumors are indeed recipients of stromal cells that have been recruited into the tumors from the systemic circulation. What are the types of stromal cells that derive from the systemic circulation, what are the signals that cause their mobilization from their niches, and what are the molecular details of how they are recruited into the tumor stroma will be investigated.
2) Epithelial:stromal interactions: A complete and detailed understanding of carcinoma pathophysiology has to involve investigations of how stromal cells and neoplastic epithelial cells interface with each other in the context of tumor initiation, maintenance, and progression. The nature of the signals exchanged between the stromal and epithelial compartments, how stromal cells become activated by cancer cells and how activated stromal cells then influence the behavior of cancer cells will be deciphered at the molecular level.
3) Stroma and metastasis: dormancy and colonization: The overwhelming majority of primary tumor cells that have disseminated throughout the circulation and that successfully invaded into the parenchyma of distant tissues remain as singletons, while only rare subsets succeed in establishing the life-threatening outgrowths of metastatic disease. This poorly-understood phenotype is likely attributable to the epithelial:stromal interactions that operate at the secondary metastatic sites, which can either lead to tumor dormancy, in which the cancer cells remain as single non-dividing cells for an extended period of time, or to the establishment of a secondary growth, perhaps akin to what occurred in the primary tumor. The molecular bases of how the process of dormancy and colonization is regulated by cancer:stroma interactions, and how such interactions differ from one 'dormant site' to another 'growth site' will be delineated.
Over the last few years, I have been able to establish and describe a model where cancer cells enlist stromal stem cells that home into primary tumors to promote cancer metastasis. Such a platform has already proven useful in elucidating, on the molecular level, how the tumor microenvironment can be usurped to facilitate metastatic progression. We will rely on this exemplary model that brings into play stem cells from both stromal and epithelial compartments, and will expand on it through the directions stated above in order to gain insight into the processes of metastasis. Such knowledge not only offers us a glimpse into cancer's most enigmatic process, but also the hope that we can one day utilize this information to design therapeutic modalities that can contain metastatic disease.
Bibliography (last five years):
1. A.E. Karnoub, M. Symons, S.L. Campbell, and C.J. Der (2004). Molecular basis for RhoGTPase signaling specificity. Breast Cancer Res. Treat. 84:61-71.
2. Singh, A., A.E. Karnoub, T.R. Palmby, E. Lengyel, J. Sondek, and C.J. Der (2004). Rac1b, a novel tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene 23: 9369-80.
3. Palmby, T.R., K. Abe, A.E. Karnoub, and C.J. Der (2004). Vav causes transformation by activation of multiple GTPases and by regulation of gene expression. Mol. Cancer Res. 2: 702-11.
4. A.E. Karnoub, E.J. Chenette, and C.J. Der (2006). Rho proteins in Ras signaling and transformation. In Ras family GTPases, Springer Pub. Co., pp. 143-167.
5. A.E. Karnoub and R.A. Weinberg (2006/7). Chemokine networks and breast cancer metastasis. Breast Dis. 26: 75-85.
6. Yohe, M.E., K.L. Rossman, O.S. Gardner, A.E. Karnoub, J.T. Snyder, S. Gershburg, L.M. Graves, C.J. Der, and J. Sondek (2007). Auto-inhibition of the Dbl-family protein TIM by an N-terminal helical motif. J. Biol. Chem. 282:13813-23.
7. Ince T.A., A.L. Richardson, G.W. Bell, M. Saitoh, S. Godar, A.E. Karnoub, J.D. Iglehart, and R.A. Weinberg (2007). Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12: 160-170.
8. A.E. Karnoub, A.B. Dash, A.P. Vo, A. Sullivan, M.W. Brooks, A.L. Richardson, K. Polyak, R. Tubo, and R.A. Weinberg (2007). Mesenchymal stem cells within tumor stroma promote breast cancer metastasis. Nature 449: 557-563.
9. C. Scheel, Onder, T., A.E. Karnoub, and R.A. Weinberg (2007). Adaptation versus selection: The origins of metastatic behavior. Cancer Res. 67: 11476-11479.
10. A.E. Karnoub and R.A. Weinberg (2008). Ras oncogenes: the split personalities. Nature Rev. Mol. Cell. Bio., 9: 517-31.