Important steps during cancer progression are tumor growth and subsequent metastasis. During tumor growth, normal cellular pathways that prevent growth and protect genome integrity are often blocked due to mutations. Conversely, pro-growth pathways are usually hyper-activated, often by acquired and, in some cases, congenital mutations. As the tumor grows, hypoxia induces the expression of growth factors that stimulate blood vessel formation into and around the tumor, further promoting growth. Subsequently, normal cell-cell interactions between the tumor and surrounding tissues and immune cells begin to breakdown, leading to invasion and eventual metastasis to distant sites. MCCB researchers focus on a number of different steps in tumor progression and metastasis, using both disease and developmental models. Research includes studies on how genome integrity is maintained and, when it is not, how transformed cells may compensate to survive and grow. MCCB labs also investigate how tumor cells interact with their local environment and how new blood vessels grow in both normal and disease settings.
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The ordering of cell cycle events is important to ensure that the genome is fully replicated before chromosomes segregate and cells divide. To achieve this ordering, many cell cycle-regulatory proteins are expressed exclusively when their functions are needed. The Benanti lab is interested in understanding why cyclical expression of key regulatory proteins is important for maintaining a stable genome. In addition, they are investigating how cell cycle-regulation of chromatin proteins helps to coordinate the condensation of chromsomes with their segregation during mitosis.
Normally, cells which have lost a classical tumor suppressor gene become highly proliferative and resistant to apoptosis, thus permitting autonomous tumor growth. However, the Bergmann Lab has discovered a novel class of tumor suppressor genes: non-autonomous tumor suppressors. If these genes are mutant, it is not the mutant cells which are overgrowing. Instead, the mutant cells influence the behavior of neighboring wild-type (non-mutant) cells and promote their proliferation and increased apoptotic resistance, causing non-autonomous overgrowth.
Metastasis suppressor genes inhibit one or more steps required for metastasis without affecting primary tumor formation. Due to the complexity of the metastatic process, the development of experimental approaches for identifying genes involved in metastasis prevention has been challenging. The Green lab developed a genome-wide RNA interference (RNAi) screening strategy that enables the discovery of new genes that regulate metastasis.
The Lewis lab is interrogating the mechanisms that underlie the progression and metastasis of hepatocellular carcinoma and pancreatic adenocarcinomas. Using a combination of cell culture models, molecular biology approaches, and in vivo modeling, the Lewis lab is characterizing the roles of novel factors involved in tumor dissemination. A current area of focus is the molecular dissection of a novel KLF6-VAV3-RAC1 signaling axis that regulates hepatocellular carcinoma invasion and metastasis.
Chen et al (2009) Differential Roles of Insulin-like Growth Factor Receptor- and Insulin Receptor-Mediated Signaling in the Phenotypes of Hepatocellular Carcinoma Cells. Neoplasia 11(9): 835-45.
Chen Y-W et al. (2013) p16 stimulates CDC42-dependent migration of hepatocellular carcinoma cells. PLOS One. 10.1371/journal.pone.0069389.
Ahronian et al. (2015) The p53R172H mutant does not enhance hepatocellular carcinoma development and progression. PLOS One.Apr 17;10(4):e0123816.
The Mercurio group is interested in the initiation and progression of epithelial-derived tumors (carcinomas), especially aggressive, poorly differentiated tumors. Their research projects emphasize molecular cell biology but they derive from the analysis and clinical behavior of carcinomas. Researchers in this group are identifying mechanisms that account for the loss of differentiation and the highly aggressive behavior of these tumors, and exploiting these mechanisms to improve prognosis and therapy. A major focus of this work is to define mechanisms that control the genesis and function of cancer stem cells with an emphasis on the role of integrin and VEGF signaling.
The Shaw lab investigates mechanisms by which carcinoma cells develop more aggressive behavior and acquire the ability to metastasize to secondary organs, with a focus on breast cancer. From a translational perspective, the goal of this work is to develop novel targets to predict or to treat metastatic cancer. The Shaw lab has had a longstanding interest in the IGF-1R/insulin signaling pathway, with a focus on the Insulin Receptor Substrate (IRS) proteins and the mechanism by which these essential signaling adaptors regulate tumor progression. A current focus in the lab is the role of the IRS proteins in cancer stem cells and their contribution to tumor metastasis.
Aneuploidy, which represents a cellular state of having an abnormal number of chromosomes, is a hallmark of cancer. The degree of aneuploidy significantly correlates with tumor aggressiveness and poor clinical prognosis. The Torres lab uses yeast as a model organism to reveal how conserved cellular processes are affected by aneuploidy. These studies will significantly improve our understanding of the role of aneuploidy in tumor biology.