Carcinogenesis

Koenraad M Van Doorslaer

Associate Professor, Immunobiology
Assistant Professor, Virology
Assistant Professor, BIO5 Institute
Assistant Professor, Cancer Biology - GIDP
Assistant Professor, Genetics - GIDP
Member of the General Faculty
Member of the Graduate Faculty
Primary Department
Department Affiliations
Contact
(520) 626-9585

Research Interest

Papillomaviruses (PVs) are a diverse family of dsDNA viruses infecting most, if not all, amniotes. Papillomaviruses infect cutaneous or mucosal epithelia. While most infections are self-limiting, persistent infection with specific human papillomaviruses has been shown to be the causative agent for cervical cancer. All established oncogenic HPV types belong to a single viral genus (the Alphapapillomaviridae). Of note, phylogenetically, these oncogenic HPV types cluster into a so-called high-risk (HR) clade, indicating an evolutionary relationship between these viruses. Importantly, not all HPV types within this HR clade are associated with cancer. I am intrigued by the observation that only a limited subset of human papillomaviruses is oncogenic. Throughout my studies I have used a combination of biochemical assays and computational analyses to understand why evolutionarily related viruses differ in their ability to cause cancer in humans. It is improbable that the ability to cause cancer provides papillomaviruses with an evolutionary advantage. It is likely that many of the viral functions linked to oncogenesis were evolutionarily beneficial as papillomavirus adapted to novel environmental niches on the host (e.g. external genitalia vs. cervix). Papillomaviruses have evolved to usurp the cellular machinery to complete their life-cycle. The papillomaviral lifecycle perturbs the normal differentiation cycle of the infected cell, forcing cells to divide far beyond their normal lifespan. It is feasible that the continued insult provided by replicating viruses eventually results in malignant transformation of the infected cell. However, while persistent infection is key to viral oncogenesis, many long-term persisting viruses do not cause cancer. By carefully interrogating the differences between these viruses, I believe it will be possible to elucidate which viral phenotypes are associated with oncogenic progression. The pathways targeted by these viruses may represent powerful targets for therapeutic intervention

Curtis Thorne

Associate Professor, Cellular and Molecular Medicine
Assistant Professor, BIO5 Institute
Member of the General Faculty
Member of the Graduate Faculty
Primary Department
Contact
(520) 626-0395

Work Summary

We combine chemical and computer vision approaches to discover how regenerative tissues process environmental information to promote accurate cell fate decisions and prevent uncontrolled cell growth.

Research Interest

We study control of cell fate and self-organization in intestinal renewal and drug response in cancer. Utilizing the fascinating characteristics of intestinal stem cells combined with chemical biology and computational image analysis approaches, we are addressing fundamental questions of multicellular systems: How do cells identify, measure, and respond to each other and to their environment? What are the signals that control the renewal and regeneration of tissues? How do these signals become defective in colorectal cancer? Our long-term goal is to uncover an underlying circuit theory behind these behaviors – a set of predictive principles that tell us how complex functionality arises from simpler biological components. We have a particular interest in kinase networks that regulate healthy tissue homeostasis and become damaged in cancer. Through our quantitative high-throughput imaging and drug discovery efforts, we are finding new ways to understand and repair these networks. Keywords: Stem cells, Cancer, Regeneration, Drug discovery

Joyce A Schroeder

Professor, Molecular and Cellular Biology
Department Head, Molecular and Cellular Biology
Professor, Cancer Biology - GIDP
Professor, Genetics - GIDP
Professor, BIO5 Institute
Primary Department
Contact
(520) 626-1384

Research Interest

My laboratory investigates the normal biology of the Epidermal Growth Factor Receptor (EGFR, and its family members, HER2 and ErbB3), as well as their role in transformation and metastasis. These oncogenes are a family of transmembrane tyrosine kinases that drive a wide-variety of cancers including HER2 positive and triple negative breast cancer, squamous cell lung cancer and glioblastoma. Our work focuses on kinase-independent activities of these receptors (such as modulation of calcium signaling and functions as transcriptional co-factors) and how the receptors are mis-regulated during cancer progression (by a loss of lysosomal degradation). These studies include investigations into receptor trafficking, nuclear translocation and protein-protein interactions that are unique to cancer survival and metastasis. We are currently focused on understanding how EGFR enters the retrotranslocation pathway that allows for it to traffic to the nucleus and directly affect gene transcription, as well as understanding how these events drive migration and survival. Based on these studies, we have developed peptide-based therapeutics for cancer that block protein-protein interactions that promote EGFR retrotranslocation. We are developing these peptide-based therapeutics for clinical applications through peptide stability studies including hydrocarbon stapling and mutational analyses. To promote the clinical translation of these discoveries, the biotech start-up company Arizona Cancer Therapeutics was founded in my lab at the Arizona Cancer Center. We are currently performing toxicity testing of our compounds with the goal of applying for approval from the FDA for clinical trials. These studies have been accomplished through the hard work and dedication of the over 50 undergraduate students, 2 MS and 11 PhD students who have studied in my lab since 2002.

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
Contact
(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.

Samuel K Campos

Associate Professor, Immunobiology
Associate Professor, Molecular and Cellular Biology
Associate Professor, Cancer Biology - GIDP
Associate Professor, BIO5 Institute
Member of the General Faculty
Member of the Graduate Faculty
Primary Department
Department Affiliations
Contact
(520) 626-4842

Work Summary

We aim to understand the mechanisms of HPV infection, the cellular responses to HPV infection, and how the interplay between host and virus influences the outcome

Research Interest

Samuel Campos, PhD, studies early events of Human Papillomavirus (HPV) infection. HPVs are small, non-enveloped DNA viruses that cause a variety of lesions ranging from benign waters to cervical cancers. Although over 100 types of HPVs have been identified, HPV16 is the most prevalent, and is alone responsible for more than 50% of cervical cancers in women worldwide. Dr. Campos and his lab study the mechanisms of HPV virus transmission at a cellular level, in hopes to discover new approaches for the prevention and treatment of HPV.HPV16 virions consist of an ~8kb circular dsDNA genome packaged into a ~60 nm protein capsid. The genome is condensed with cellular histones and exists in a chromatin-like state. The capsid is comprised of 72 pentamers of the major capsid protein L1 and up to 72 molecules of the minor capsid protein L2, localized along the inner capsid surface, within the central cavities beneath the L1 pentamers. Mature HPV16 virions exist in an oxidized state, with adjacent L1 pentamers crosslinked together by disulfide bonds to stabilize the capsid. In order to establish an infection, HPV16 virions must bind and penetrate host cells, ultimately delivering their genomes to the host cell nucleus to initiate early gene expression, cell cycle progression, and genome replication. Non-enveloped viruses are faced with the challenge of getting their genetic material across a cellular membrane and often overcome this by disrupting the endosomal or lysosomal membranes and translocating to the cellular cytoplasm during the course of intracellular virion trafficking. Keywords: virology, microbiology, virus-host interaction, HPV