Cancer Cell Biology Program Scientific Achievements, 2006-2007

Overview

From Oct. 1, 2006-Sept. 30, 2007, members of Cell Biology published more than 120 full-length, peer-reviewed cancer-related papers, with 27 of these appearing in high-visibility journals, such as Cancer Cell, Cancer Research, EMBO Journal, Development, Molecular Cell, Oncogene and Molecular Cancer Therapeutics.  Of these, 39 (33%) were inter-programmatic or inter- and intra-programmatic publications; 8 (7%) were intra-programmatic or inter- and intra-programmatic publications. View the list of publications.

Program activities are critical to the scientific progress of the Program membership because they promote interactions that would not otherwise take place.  Activities occur at two levels:

1. a seminar program and minisymposia for the entire Cell Biology membership (and other Cancer Center members), and
2. discussion groups and journal clubs within the program's three subgroups. 

The seminar program entitled "Cells, Development and Cancer" features seminars by outstanding invited speakers. A consortium of four interest groups, including the Cancer Center, has made this series possible.  Examples of important speakers in last year are:

• Thomas Look, M.D. (Dana Farber Cancer Center) “A Zebrafish model of  Cancer”
• David Stern, Ph.D. (Yale) “Erb2 and Breast Cancer Therapy”
• Martin Rechsteiner (Univ. of Utah) “The Proteosome”
• Ellen Fanning, Ph.D. (Vanderbilt) “Simian virus 40 hijacks DNA repair pathways to replicate its minichromosome"

We also continue to sponsor a number of “interest groups” such as “Cell Cycle Club” (Dr. Sclafani) and the “Leukemia Focus Group” (Dr. DeGregori), in which lab members present their work in an informal setting.

Proliferation and Apoptosis

New full members in this group are Drs. Shellman, Wright, Gu and Koch.

Dr. Shellman studies apoptosis and melanoma. She investigates how activation of Ras or its effector pathways (Braf/MEK/ERK and PI3K/Akt) control anti-apoptotic defense, and whether these regulation contribute to melanoma resistance to therapy. These signal pathways are one of the most important pathways associated with high frequency of mutations in melanomas. She is also involved in developing a yeast-based vaccine against melanoma (Rieman et al., 2007) as is Dr. Franzusoff in collaboration with Drs. Bellegrau (II) and Duke (II) (Haller et al., 2007).

Dr. Shellman used yeast cells as an efficient vehicle of antigen loading and immunostimulation to develop a melanoma vaccine and tested it in a mouse pre-clinical model. S. cerevisiae is not pathogenic to humans and can be easily engineered to express specific antigens. Despite the lack of knowledge of dominant epitopes of the protein recognized by mouse MHC-class I, the vaccine protected mice from tumor development and induced efficient immune responses, suggesting that the precise knowledge of epitopic sequences and the matched HLA type is not required when delivering a full-length protein expressed in yeast. The vaccine stimulated cellular immunity in that CD4(+) T cells and CD8(+) T cells were activated. Her study provided a 'proof of principle' that recombinant yeast can be utilized as an effective prophylactic vaccine to target patients at high-risk for melanoma.

Dr. Wright analyzes lung damage by cytokines as mediated by integrins (Pamley et al, 2007). 

Drs. DeGregori, Schiemann, Sorkin (Fellowship) and Espinosa have obtained new NCI grants in the last year.

Drs. Reyland, Schiemann, DeGregori, Cheng, Liu, Klymkowsky and Sclafani received seed grants from the Cancer Center. Some of their studies will be described below.

Dr. DeGregori continues his NCI-funded study of the genetic basis of leukemia and has proposed that cell fitness in addition to mutations is important in cancer development (Marusyk and Degregori, 2006). His hypothesis can explain the relationship between aging and cancer and the role of the p53 tumor suppressor (Marusyk and Degregori, 2006). Recently, Dr. DeGregori’s laboratory has peformed a screen for genes that interact with the Bcr-Abl oncogene. He has used a shRNA knockdown library to find genes that increase sensitivity to Gleevac, a Bcr-Abl antagonist used to treat leukemia. The goal of his study to identify new targets to increase the effectiveness of Gleevac treatent and to provide possible therapeutic intervention when Gleevac resistance occurs.

Dr. Graham has collaborated with Drs. Greffe (PC) and Garrington (CB) to study natural killer cell leukemia (Liang et al., 2007).

Dr. Espinoza also studies p53-depdendent transcription and Apoptosis with NCI-support (Donner et al., 2007; Kalet et al., 2007). His genome-wide studies have revealed new targets for p53-based therapy. He is collaborating in this project with Dr. Bentley (MO), an expert in transcriptional regulation.

Dr. Thorburn has collaborated with Drs. Anderson SM (HRM,CB) and Kassenbrock CK (CB) (Lyons et al, 2007) in studying the role of Akt oncogene in apoptosis with NCI support. He also has collaborated with Drs. Behbakht (HRM), Davidson (HRM), and Ford (HRM) to find that oncogene Six1 overexpression in ovarian carcinoma causes resistance to apoptosis and is associated with poor survival (Behbakht et al., 2007). In this case, the expertise of the two investigators synergized. Dr. Ford (HRM) is an expert in the study of the Six1 oncogene and Dr. Thorburn is an expert in TRAIL-mediated apoptosis. In Dr. Ford’s microarray-based study of genes regulated by Six1, she discovered the connection with TRAIL-mediated apoptosis and then collaborated with Dr. Thorburn. They also screened normal ovarian and carcinoma specimens and found overexpressed Six1 in 50% of the early-stage (stage I) and 63% of the late-stage (stages II, III, and IV) ovarian carcinomas. In patients with late-stage disease, high Six1 expression indicated a poor prognosis. This study is a fine example of translational research at its best as it goes from the laboratory to provide important diagnostic and prognostic information in the clinic. 

Dr. Sclafani continues his successful collaboration with Dr. Agarwal (HRM,CC) in studying the mechanism of cancer chemoprevention by the natural product, Silibinin (Roy et al., 2007) with NCI-support. They provided molecular evidence that Silibinin acts by blocking cell cycle progression by increasing the level of the Cip/Kip family of inhibitors. They also are interacting with Drs. Glode (HRM) and Raben to use a pre-clinical animal model to test if the natural compound Resveratrol can be used to increase the efficacy of radiation in treatment of head and neck cancers. Their studies are based on their previous work showing that Resvertrol activates the DNA damage checkpoint in ovarian cancer cells (Tyagi et al., 2005). Along these lines, Dr. Sclafani has obtained a seed grant from the UCCC to investigate the effect of Resveratrol on aging and DNA damage checkpoint.

Dr. Harrison also collaborated with Dr. Agarwal (HRM,CC) and Drs. Flaig (DT) and Glode (HRM) in studying how Silibinin in vitro in human prostate cancer cells (Flaig et al., 2007) and with Drs. Gustafson (DT), Agarwal (HRM,CC), and Glode (HRM) using Silibinin in a Phase 1 clinical trial (Flaig et al, 2007).

Dr. Schiemann's elegant studies continue to reveal the role of TGF-Beta in cellular transformation and the possibility of TGF-Beta-based chemotherapy with NCI-support (Schiemann, 2007; Galliher and Schiemann, 2007). He showed that beta(3) integrin interacted physically with the TGF-beta type II receptor (TbetaR-II), leading to its tyrosine phosphorylation by Src and the initiation of oncogenic signaling by TGF-beta. Oncogenic Src phosphorylated TbetaR-II on Y284 both in vitro and in vivo. Interestingly, although the expression of Y284F-TbetaR-II mutants in breast cancer cells had no effect on TGF-beta stimulation of Smad2/3, this TbetaR-II mutant completely abrogated p38 MAPK activation by TGF-beta. Accordingly, Src-mediated phosphorylation of Y284 coordinated the docking of the SH2 domains of growth factor receptor binding protein 2 (Grb2) and Src homology domain 2 containing (Shc) TbetaR-II, thereby associating these adapter proteins to MAPK activation by TGF-beta. Importantly, Y284F-TbetaR-II mutants also abrogated breast cancer cell invasion induced by alpha(v)beta(3) integrin and TGF-beta as well as partially restored their cytostatic response to TGF-beta. These studies discovered that a novel alpha(v)beta(3) integrin/Src/Y284/TbetaR-II signaling axis that promotes oncogenic signaling by TGF-beta in malignant MECs that antagonizes this signaling axis. Thhis discovery may one day prove beneficial in treating patients with metastatic breast cancer.

Dr. Liu has collaborated with Drs. Kappler (II) and Marrack (II)  in studying the role of the oncogene Bcl-x in apoptosis in T-cells (Liu et la., 2006). Dr. Liu also continues his studies of the Smad-signalling oncogene pathway in cancer, which regulates TGF-Beta (Zhu et al., 2007) with NCI-support.

Membrane Receptors and Traffic

This focus group continues to be important in cancer research especially with the advent of growth factor therapies that employ EGF and erbB2 inhibitors such as Gefitinib (Iressa) and Trastuzumab (Herceptin), respectively. These receptors are transmembrane proteins that are selectively accumulated in clathrin-coated pits at the plasma membrane and rapidly internalized in clathrin-coated vesicles. Many cancer cells may become resistant to these therapies because of defects on normal receptor turnover and recycling.

Dr. Liu has collaborated with Dr.Thor AD (HRM) to show that downregulation of receptor erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells (Liu et al., 2007). They showed that erbB2/erbB3 heterodimerization is needed for erbB2 tyrosine kinase activation in breast cancer cells and that downregulation of erbB3 inhibits erbB2-associated procarcinogenic activity via inactivation of the PI-3K/Akt pathway. Importantly, erbB3 contributes to erbB2-mediated tamoxifen resistance and could be a clinically relevant therapeutic target in addition to erbB2. The clinical significance of their work is high as erbB2, which is a oncogene is human breast cancer and tamoxifin is already used in ER-postive tumors.

Dr. Sorkin continues his analysis of receptor mediated endocytosis and turnover by protein ubiquitination (Miranda and Sorkin, 2007; Sorkin, 2007) with NCI-support. He has shown that PKC (protein kinase C), an important signal transduction enzyme, regulates DAT (dopamine transporter) internalization and recycling by affecting DAT ubiquitylation. This is the first example in which ubiquitin conjugation of DAT creates a molecular interface with the cellular endocytic machinery.

Development and Cancer

It is clear that many proteins important during normal cell development and differentiation are mis-regulated in cancer cells. Several groups are studying these molecules and how they affect tumorigenesis.

Dr. Anderson collaborated with Drs. McManaman (HRM) and Neville (HRM) to study mammary gland neoplasia in mice transgenic for the Akt oncogene (Palmer et al., 2006; Anderson et al., 2007). They used genetically altered mice to study both mammary gland development during puberty and pregnancy and mammary tumorigenesis. They have established a sophisticated array of molecular genetic technologies to accomplish these goals. For example, they used knockout animals and transgenic animals with mammary-specific expression to investigate the role of the Akt oncogene is normal mammary epithelial cell development. They showed that Akt acts together with SREBP1 protein to regulate secretory activation of lipid biosynthesis and thereby to support the nutritional needs of the newborn. Any therapy that targets Akt will have to consider the importance of Akt in normal mammary function, which is the focus of their studies.

Dr. Schedin with Dr. Borges (II) discuss similar findings about the relationship between the normal process of mammary gland involution and breast cancer progession (Schedin et al., 2007)

Dr. Klymkowsky investigated the regulation of the important transcription factor, NF-kappaB in the early vertebrate mesoderm (Zhang et al., 2006). Transcription factor NF-kappaB is known to have many roles in cancer development and studying its cellular role in this context will yield valuable information. They used morpholino-based (RNAi) loss of function studies to show that the Slug protein is an important regulator in the NF-kappa B pathway in both development and metastasis. The function of the important oncogene Bcl-xL is dependent upon NF-kappaB, which directly regulates levels of Slug and Snail RNAs Their studies show that a Slug/Snail-NF-kappaB regulatory circuit is active during mesodermal formation in Xenopus. Their proposed regulatory schema have significance for normal development and the progression to metastatic disease. Dr. Klymkowsky also received a UCCC seed grant to investigate new aspects of this important regulation and how it can be exploited for cancer therapeutic intervention.

Future Plans

Both the Departments of Biochemistry and Molecular Genetics (BMG) and Cell and Developmental Biology (CDB) have many members in CCB and are in the process of recruiting new Chairs. The program leader will continue to emphasize the importance of cancer research in these two recruitments and to communicating with the candidates that the cancer center is committed to helping to recruit new faculty with a cancer focus. As Interim Chair of BMG, Dr. Sclafani is involved in both searches and will meet with the candidates. In addition, Dr. Thorburn is a member of the CDB search committee.

UCCC Cores

Cancer Cell Biology members could not accomplish their work without using the Tissue Culture, Flow Cytometry, DNA Sequencing and Analysis, Proteomics, and Laboratory Animal Cores. The program leader communicates with Dr. Thorburn, Associate Director of Basic Sciences regarding any problems with these cores. He also queries the membership about any problems or desired new technologies and then meets with both core directors and Dr. Thorburn.