How do tumors grow and spread?
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.
Click below to see learn more about MCCB research in this area.
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.
- Herzet al. (2006). vps25 mosaics display non-autonomous cell survival and overgrowth, and autonomous apoptosis. Development 133, 1871-1880.
- Lee et al. (2008). The E1-ubiquitin-acitivating-enzyme uba1 in Drosophila controls apoptosis autonomously and tissue growth non-autonomously. Development 135, 43-52.
- Christiansen et al. (2012). Ligand-independent activation of the Hedgehog pathway displays non-autonomous proliferation and differentiation during eye development in Drosophila. Mechanisms of Development 129, 98-108.
- Christiansen et al. (2013). Non-autonomous and context-dependent control of apoptosis by deregulated Hedgehog signaling in Drosophila. Cell Death & Differentiation 20:302-11.
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.
- Gobeil et al. (2008) A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene. Genes Dev, 22(21):2932-40.
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.
- Goel HL, Chang C, Pursell B, Leav I, Lyle SR, Xi HS, Hsieh CC, Adisetiyo H, Roy-Burman P, Coleman IM, Nelson PS, Vessella RL, Davis R, Plymate SR, Mercurio AM. VEGF/Neuropilin-2 regulation of Bmi-1 and repression of IGF-1R define a novel mechanism of aggressive prostate cancer. (2012) Cancer Discovery, 2012, 2:906-921.
- Goel HL, Gritsko T, Pursell B, Chang C, Shultz LD, Greiner DL, Norum JH, Toftgard R, Shaw LM, Mercurio AM. (2014) Regulated splicing of the a6 integrin cytoplasmic domain determines the fate of breast cancer stem cells and tumor initiation. Cell Reports 2014, 7:747-761.
- Chang C, Goel HL, Gao H, Pursell B, Shultz LD, Greiner DL, Pattaryo M, Mao J, McKee KK, Yurchenco PD, Mercurio AM. (2015) A laminin 511 matrix is regulated by TAZ and functions as the ligand for the a6Bb1 integrin to sustain breast cancer stem cells. Genes and Development, 29:1-6.
The Shaw lab investigates mechanisms by which carcinoma cells acquire the ability to metastasize, with a focus on breast cancer. We have had a longstanding interest in 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 understanding the structure of the IRS proteins to determine how they regulate tumor cell functions, such as cancer stem cell self-renewal and invasion, that contribute to metastasis.
- Mercado et al. (2017) Differential involvement of the microtubule cytoskeleton in Insulin Receptor Substrate-1 (IRS-1) and IRS-2 signaling to AKT determines response to microtubule disruption in breast carcinoma cells. J. Biol. Chem, 292:7806-7816.
- Zhu et al. (2018) Novel IRS2 mutations contribute to pleomorphic invasive lobular breast cancer. JCI Insight, 3(8): e97398 doi:10.1172;jci.insight.97398.
- Mercado-Matos et al. (2018) Identification of a novel invasion-promoting region in Insulin Receptor Substrate 2 (IRS2). Mol. Cell. Biol. 38(14): e00590-17. doi:10.1128/MCB.00590-17.
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.
- Torres et al. (2007). Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science. 317, 916-924.
- Torres et al. (2010). Identification of aneuploidy-tolerating mutations. Cell. 143, 71-83.