mPI: Alicia Bolt, PhD
Alicia Bolt, PhD is an assistant professor at the College of Pharmacy. The Bolt lab is focused on metal toxicology using both in vitro and in vivo models. The current research interests of the lab are on determining the molecular mechanisms of how environmental metals can advance tumor progression by targeting the surround tumor microenvironment and how mixed metal exposures leads to immune dysfunction. The Bolt lab is highly experienced in the use of primary cell differentiation models and multi-parameter flow cytometry as tools to characterize metal-induced toxicity and disease states.
Project Summary
Tungsten is an emerging toxicant, due to increased human exposure, yet limited knowledge of the human health risks. One large research gap is our lack of knowledge of the carcinogenic/tumorigenic risks of tungsten exposure. Importantly, a few in vivo studies do suggest that tungsten can enhance tumor promotion. However, more research is needed to determine which forms and routes of exposure of tungsten can drive tumorigenesis and the underlying cellular/molecular mechanisms of action. An accidental exposure of breast cancer patients to tungsten following experimental radiotherapy, prompted us to investigate the role of tungsten on breast cancer progression and metastasis, by conducting an animal study using an aggressive orthotopic mammary cancer mouse model. Oral tungstate exposure enhanced breast cancer metastasis to the lung and increased growth at the metastatic site. Interestingly, tungsten-enhanced metastasis was associated with enhanced stroma in the tumor microenvironment, importantly, cancer-associated fibroblasts (CAFs) that are known to drive tumor progression. Our research identified, for the first time, a potential cellular mechanism of action for tungsten-enhanced tumor promotion. However, what role the CAFs plays in this complex process remains to be elucidated. This proposal will use a novel, integrative approach to investigate when and how tungsten targets the tumor microenvironment to promote breast cancer. AIM 1 I will evaluate how different forms of tungsten (oral tungstate, inhaled tungsten carbide and implantation tungsten metal fragments) target the tumor microenvironment to affect breast cancer progression from initiation to metastasis. I will extend my initial findings to determine how different forms of tungsten alter breast cancer development, growth and metastasis to multiple sites including lung, liver, bone, and brain. AIM 2, I will measure CAF activation following tungsten exposure in vitro. I will address the following questions. Can tungsten enhance CAF activation from stromal precursors? Do tungsten-exposed CAFs enhance tumor cell invasion, growth, and immune cell recruitment? And, does tungsten alter tumor cell cues to enhance CAF activation and/or recruitment? Finally, in AIM 3 I will test the impact of tungsten-altered CAFs to enhance metastasis in an in vivo model. I will determine if tungsten-altered CAFs promote metastasis and growth in the lung niche by answering the following questions. What is the source of tungsten-enhanced CAFs in the lung niche? Do CAFs from the lung niche of tungstenexposed tumor-bearing mice have an altered cytokine/chemokine profile? And, are CAFs critical mediators of tungsten-enhanced lung metastasis? Completion of this proposal will extend our toxicological knowledge of tungsten to determine how different forms of tungsten impact breast cancer progression and define the role of the tumor microenvironment, particularly CAFs in tungsten-enhanced breast tumorigenesis. This work will also identify a novel cellular mechanism of action that can expand our knowledge of how environmental toxicant can drive tumorigenesis and develop new therapeutic interventions.
mPI: Xixi Zhou, PhD
Xixi Zhou, PhD is an assistant professor at the College of Pharmacy. The Zhou lab is primarily interested in 1) the molecular mechanism of arsenite-induced toxicology and carcinogenesis, 2) the involvement of oxidative/nitrosative stress and protein oxidation/nitrosation in cancer development, and 3) mass spectrometry (MS)-based proteomic analyses for metal-protein interactions.
Project Summary
Arsenic is a major factor for increased risk of several human health problems, including cancers of the liver, urinary tract, skin, and lung, among which lung cancer is the leading cause of cancer mortality. Particulate arsenic trioxide (pATO) is frequently observed as a component of ambient particulate matter (PM), specifically in dust arising from unremediated surface mine sites and tailings piles, both of which are common in the southwestern US. Soluble arsenite ingestion and low-solubility pATO inhalation both lead to an increased risk of lung cancer development. Although pATO inhalation is an exposure route more relevant to lung carcinogenesis, there are very few studies investigating the biological impact of pATO. Moreover, the underlying molecular mechanisms of arsenic-induced lung carcinogenesis remain unknown. Previous studies exploring the carcinogenic properties of soluble arsenic may significantly underestimate the human health risks associated with pATO inhalation. The long-term goal of this work is to provide quantitative information for risk assessment and to facilitate prevention of the adverse health effects of inhaled particulate arsenic in human populations. The aim of the current proposal is to elucidate the carcinogenic mechanisms of pATO exposure. Our preliminary findings reveal that at the same concentration, pATO generates significantly more reactive oxygen species (ROS) and yields higher DNA damage than soluble arsenic. Thus, we hypothesize that particulate arsenic has greater potential to incite lung carcinogenesis than soluble arsenic through combination effects of oxidative stress; DNA damage and DNA repair inhibition. Moreover, our preliminary results confirm, for the first time, that exposure to arsenic at an environmentally relevant level is sufficient to generate a unique spectrum of somatic mutations on the genome. The current proposal aims to analyze mutational signatures arising from pATO exposure as the readout of mutational processes and subsequent operative repair processes. To this end, we propose the following specific aims: Aim 1: To assess the higher potency of pATO in terms of ROS induction and oxidative DNA damage. Aim 2: To analyze mutational signatures of pATO exposure and DNA repair mechanisms including alterations in DNA binding sequence specificity of DNA repair proteins such as PARP-1. Aim 3: To evaluate the transformation and mutagenicity effect of chronic particulate arsenic exposure in lung epithelial cells using whole exome sequencing (WES) to identify mutations and deletions on protein-coding genes associated with transformation. Successful completion of these aims will improve our scientific knowledge of particulate arsenic-induced lung carcinogenesis by identifying cell specific mutational signatures and their causes, including synergistic actions of oxidative stress, DNA damage, and DNA repair inhibition.
mPI: Xiang Xue, PhD
Xiang Xue, PhD is an assistant professor in the Department of Biochemistry & Molecular Biology. His lab is focused on studying molecular mechanisms for inflammatory bowel disease (IBD) and colorectal cancer (CRC). He utilizes cell lines and enteroid cultures, mouse models, patient tissues and a wide array of molecular and biochemical methodologies. The long term goals of his research are to understand how micronutrients, particularly iron, interact with macronutrients and intestinal cells and to leverage this knowledge to develop novel therapeutics to treat colitis and colorectal cancer without altering systemic nutrient homeostasis.
Project Summary
Colorectal cancer (CRC) is the third leading cause of cancer-related death in US. Understanding the mechanisms of CRC development is essential to improve treatment. Increased tissue iron in both mice and humans is associated with increased colon tumorigenesis. However, the precise mechanisms for how iron contributes to colon carcinogenesis are still unclear. The metabolic differences between normal and cancer cells are being interrogated to uncover potential new therapeutic approaches. Many tumor cells exhibit increased glucose consumption, glutamine metabolism and nucleotide synthesis. This proposal will test the central hypothesis that iron-driven cellular metabolic reprograming promotes DNA synthesis and colon tumorigenesis. This hypothesis is based on: 1) iron supplement increases, whereas chelation of iron by deferoxamine (DFO) inhibits the growth and cell proliferation of patient-derived CRC colonoids; 2) treating mice with high-iron diet increases, while low-iron diet decreases colon tumor multiplicity, incidence and progression; 3) metabolomics analysis reveals that excess iron impacts glucose-stimulated nucleotide synthesis by promoting hypoxia-independent “Warburg-like effect” and fueling pentose phosphate pathway in colonoids; 4) iron restriction by DFO leads to glutamine accumulation and reduction of metabolites in nucleotide biosynthesis pathways in colonoids. Based on these observations, the proposal will test the following three Specific Aims: 1) Define the mechanism by which excess iron affects glucose-stimulated DNA biosynthesis in CRC; 2) Study the impact of iron restriction on glutamine-dependent nucleotide synthesis in CRC; 3) Characterize the role of a DNA polymerase in iron-regulated nucleotide metabolism and CRC. We will utilize highly clinic-relevant CRC patient-derived colonoid culture, metabolomics analysis, and various animal models. Accomplishing the above Aims will provide precise molecular mechanisms for how tumor cells are adapted to iron signal to synthesize nucleotides for facilitating tumor proliferation. These studies will fill our knowledge gap of how iron regulates CRC growth and progression.
mPI: Rama Gullapalli, MD, PhD
Dr. Gullapalli is an Assistant Professor in the departments of Pathology and Chemical and Nuclear Engineering at the University of New Mexico (UNM). The Gullapalli lab is highly interested in the convergence of emerging technologies with traditional clinical and pathology practice within the domain of clinical genomics and bioinformatics. The lab is currently focused in two areas of research 1) Basic cancer biology of Hepatobiliary cancers using high throughput techniques of next generation sequencing and 2) Development of non-invasive, high sensitivity techniques for capture and analysis of circulating DNA in Hepatobiliary cancer patients. The Gullapalli lab uses a wide variety of techniques such as high-throughput sequencing, bioinformatics, molecular biology, nanoparticle synthesis, and systems biology to understand the underlying mechanisms driving Hepatobiliary cancers.
Project Summary
Gallbladder Cancer (GBC) is the fifth most common malignancy of the GI tract and the most common in the human biliary tree. Approximately 4,000-5,000 new cases of GBC are diagnosed in the United States annually. Survival outcomes are dismal with only ~8% 5-year survival rate, making it one of the deadliest cancers. GBC has a distinct geographical incidence pattern with global hotspots. These hotspots include countries like Chile, Bolivia, India and the state of New Mexico (NM) in the United States. GBC incidence is abnormally high among the “minority-majority” Native Americans (5-8 fold higher) and Hispanics (2-4 fold higher) compared to Caucasians living in New Mexico. The reasons underlying GBC incidence disparities in NM is unknown and there are critical gaps in our understanding of gallbladder carcinogenesis. We postulate environmental heavy metal exposure is the key risk factor responsible for GBC disparities seen among minorities of NM. The southwestern United States (NM, AZ, UT and NV) has a long environmental legacy of abandoned heavy metal mines. These mines are usually found in close proximity to a significant number of socio-economically disadvantaged Native American and Hispanic communities of NM. To prove our GBC hypothesis, we propose the use of New Mexican patient derived gallbladder epithelial cell lines in this proposal. Aim 1 will use post-surgical gallbladder samples to determine the somatic mutational landscapes and key molecular drivers of GBC in an ethnicity and gender dependent manner. Aim 2 will determine the impact of exposures of two metals of significance in New Mexico, uranium and cadmium, on the GB phosphoproteomic cell signaling dysregulation. In particular, we will focus on the role of metal exposure driven PI3K-Akt and MAPK signaling pathway alterations. Aim 3 will determine the effects of cadmium and uranium exposure on gallbladder epithelial barrier disruption and wound healing as a mechanistic explanation of GBC disparities seen in NM. Aim 3 will confirm, for the first time, the role of metal induced disruption of the GB epithelial barrier causing chronic transmural inflammation which is a well-known prerequisite of gallbladder carcinogenesis. Our long-term goal is to understand the molecular mechanisms of gallbladder carcinogenesis using innovative, high-throughput bioinformatics approaches. This basic science proposal deeply informs the translational clinical initiatives currently underway in our lab. Finally, this proposal will also provide a firm scientific basis to enable preventative, population-based screening measures to alleviate GBC disparities seen in Native American and Hispanic communities of New Mexico.
