Bernard W Futscher
Assistant Research Scientist, Cancer Center Division
Associate Professor, BIO5 Institute
Investigator, Center for Toxicology
Professor, Pharmacology and Toxicology
Professor, Cancer Biology - GIDP
Primary Department
Department Affiliations
(520) 626-4646
Work Summary
Bernard Futscher's lab is studying the molecular origins of human cancer. Understanding epigenetic dysfunction in human cancer has been Dr. Futscher's primary research focus since establishing his own independent laboratory. This epigenetic research has moved into the area of noncoding RNAs and their potential role in cancer cell immortality.
Research Interest
Bernard Futscher, PhD, and his lab focus on the molecular origins of human cancer. More specifically, the lab group has 3 inter-related research objectives based on the underlying concept that developing an in-depth understanding of epigenetic mechanismsresponsible for governing cell fate will allow for the development of more effective strategies for the prevention, treatment, and cure of cancer. First, they wish to identify which epigenetic mechanisms participate in the transcriptional control of genes important to growth and differentiation. Second, they seek to determine how these epigenetic mechanisms, and therefore epigenetic homeostasis, become compromised during oncogenesis. Third, using a new and more complete understanding of epigenetic control of the genome, Dr. Futscher and his team are developing rational new therapeutic strategies that seek to repair these defects in the cancer cell and transcriptionally reprogram the malignant cancer cell to a benign state. To reach their objectives, a variety of in vitro models of cancer have been developed to address emerging hypotheses that are inferred from the literature in basic and clinical science as well as our own data. Results from these in vitro studies are then translated to the clinical situation to determine their meaning in the actual clinical face of the disease. Similarly, they attempt to take information obtained from the genome-wide assessment of clinical specimens in order to help guide our thinking and develop new hypotheses that can be tested experimentally in our in vitro models.

Publications

Jeixun, L. i., Hua, S. u., Chen, H., & Futscher, B. W. (2007). Optimal search-based gene subset selection for gene array cancer classification. IEEE Transactions on Information Technology in Biomedicine, 11(4), 398-405.
BIO5 Collaborators
Hsinchun Chen, Bernard W Futscher

PMID: 17674622;Abstract:

High dimensionality has been a major problem for gene array-based cancer classification. It is critical to identify marker genes for cancer diagnoses. We developed a framework of gene selection methods based on previous studies. This paper focuses on optimal search-based subset selection methods because they evaluate the group performance of genes and help to pinpoint global optimal set of marker genes. Notably, this paper is the first to introduce tabu search (TS) to gene selection from high-dimensional gene array data. Our comparative study of gene selection methods demonstrated the effectiveness of optimal search-based gene subset selection to identify cancer marker genes. TS was shown to be a promising tool for gene subset selection. © 2007 IEEE.

Eblin, K. E., Hau, A. M., Jensen, T. J., Futscher, B. W., & Gandolfi, A. J. (2008). The role of reactive oxygen species in arsenite and monomethylarsonous acid-induced signal transduction in human bladder cells: Acute studies. Toxicology, 250(1), 47-54.

PMID: 18588940;PMCID: PMC2567114;Abstract:

Arsenicals are known to induce ROS, which can lead to DNA damage, oxidative stress, and carcinogenesis. A human urothelial cell line, UROtsa, was used to study the effects of arsenicals on the human bladder. Arsenite [As(III)] and monomethylarsonous acid [MMA(III)] induce oxidative stress in UROtsa cells after exposure to concentrations as low as 1 μM and 50 nM, respectively. Previous research has implicated ROS as signaling molecules in the MAPK signaling pathway. As(III) and MMA(III) have been shown to increase phosphorylation of key proteins in the MAPK signaling cascade downstream of ErbB2. Both Src phosphorylation (p-Src) and cyclooxygenase-2 (COX-2) are induced after exposure to 50 nM MMA(III) and 1 μM As(III). These data suggest that ROS production is a plausible mechanism for the signaling alterations seen in UROtsa cells after acute arsenical exposure. To determine importance of ROS in the MAPK cascade and its downstream induction of p-Src and COX-2, specific ROS antioxidants (both enzymatic and non-enzymatic) were used concomitantly with arsenicals. COX-2 protein and mRNA was shown to be much more influenced by altering the levels of ROS in cells, particularly after MMA(III) treatment. The antioxidant enzyme superoxide dismutase (SOD) effectively blocked both As(III)-and MMA(III)- associated COX-2 induction. The generation of ROS and subsequent altered signaling did lead to changes in protein levels of SOD, which were detected after treatment with either 1 μM As(III) or 50 nM MMA(III). These data suggest that the generation of ROS by arsenicals may be a mechanism leading to the altered cellular signaling seen after low-level arsenical exposure. © 2008 Elsevier Ireland Ltd. All rights reserved.

Davis, T. L., Rabinovitz, I., Futscher, B. W., Schnölzer, M., Burger, F., Liu, Y., Kulesz-Martin, M., & Cress, A. E. (2001). Identification of a Novel Structural Variant of the α6 Integrin. Journal of Biological Chemistry, 276(28), 26099-26106.

PMID: 11359780;PMCID: PMC2824502;Abstract:

The α6 integrin is a 140-kDa (nonreduced) laminin receptor. We have identified a novel 70-kDa (nonreduced) form of the α6 integrin called α6p for the latin word parvus, meaning small. The variant was immunoprecipitated from human cells using four different α6-specific monoclonal antibodies but not with α3 or α5 antibodies. The α 6p integrin contained identical amino acid sequences within exons 13-25, corresponding to the extracellular "stalk region" and the cytoplasmic tail of the α6 integrin. The light chains of α6 and α6p were identical as judged by α6A-specific antibodies and electrophoretic properties. The α6p variant paired with either β1 or β4 subunits and was retained on the cell surface three times longer than α6. Reverse transcription/polymerase chain reaction analysis revealed a single polymerase chain reaction product. The α6p variant was found in human prostate (DU145H, LnCaP, PC3) and colon (SW480) cancer cell lines but not in normal prostate (PrEC), breast cancer (MCF-7), or lung cancer (H69) cell lines or a variant of a prostate carcinoma cell line (PC3-N). Protein levels of α6p increased 3-fold during calcium-induced terminal differentiation in a normal mouse keratinocyte model system. A novel form of the α6 integrin exists on cell surfaces that contains a dramatically altered extracellular domain.

Domann, F. E., & Futscher, B. W. (2003). Editorial: Maspin as a molecular target for cancer therapy. Journal of Urology, 169(3), 1162-1164.
Futscher, B., Jensen, T. J., Novak, P., Eblin, K. E., Gandolfi, A. J., & Futscher, B. W. (2008). Epigenetic remodeling during arsenical-induced malignant transformation. Carcinogenesis, 29(8).

Humans are exposed to arsenicals through many routes with the most common being in drinking water. Exposure to arsenic has been associated with an increase in the incidence of cancer of the skin, lung and bladder. Although the relationship between exposure and carcinogenesis is well documented, the mechanisms by which arsenic participates in tumorigenesis are not fully elucidated. We evaluated the potential epigenetic component of arsenical action by assessing the histone acetylation state of 13 000 human gene promoters in a cell line model of arsenical-mediated malignant transformation. We show changes in histone H3 acetylation occur during arsenical-induced malignant transformation that are linked to the expression state of the associated gene. DNA hypermethylation was detected in hypoacetylated promoters in the select cases analyzed. These epigenetic changes occurred frequently in the same promoters whether the selection was performed with arsenite [As(III)] or with monomethylarsonous acid, suggesting that these promoters were targeted in a non-random fashion, and probably occur in regions important in arsenical-induced malignant transformation. Taken together, these data suggest that arsenicals may participate in tumorigenesis by altering the epigenetic terrain of select genes.