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Mission of the Program in Cancer Biology

To train new leaders in the field of Cancer Biology that will develop new knowledge that will translate into improved detection, diagnosis, prognosis, prevention, or treatment of cancer.

Research Areas of Emphasis

  • Cancer Immunity, host tumor interactions, and angiogenesis
  • Cancer Precision Medicine—targeted therapies and drug resistance using mouse modeling, human tumor tissues, and systems approaches
  • Bioinformatic analyses of tumor heterogeneity including genome, proteome, metabolome, and immunome components during tumor progression
  • Basic Cancer Biology—tumor progression, invasion and metastasis

Steering Committee

Ann Richmond, Program Director
Jin Chen, Director of Graduate Studies
Barbara Fingleton
Rachelle Johnson
Kimryn Rathmell
Julie Sterling
Alissa Weaver
Chris Williams

 

News & Events

Nicholas Markham, MD, PhD
Assistant Professor of Medicine, Assistant Professor of Pathology, Microbiology, & Immunology Division of Gastroenterology, Hepatology, & Nutrition.
Program in Cancer Biology.
Staff Physician, TVHS-Veterans Affairs.
Dr. Markham is a newly appointed faculty member in the Program in Cancer Biology. His basic science laboratory investigates the mechanistic relationships between colonic microbes and host cells. He uses in vivo approaches spanning mouse models of gastrointestinal infections to colorectal cancer and 3-dimensional human organoid tissue culture to understand how keystone bacterial species dysregulate host epithelial cell homeostasis. Specifically, these endeavors  developed during his postdoctoral fellowship with Dr. Borden Lacy, and Dr. Robert Coffey in a project focused on determining how C. difficile toxin B (TcdB) transactivates colonic growth factor signaling pathways during pathogenesis. His preliminary data are the foundation for his current VA Career Development Award. The long-term goal is to reveal targets for therapeutic or preventive strategies that predict C. difficile pathogenesis. In addition, Dr. Markham has collaborated with Dr. Cindy Sears and Dr. Julia Drewes of Johns Hopkins University to investigate the role of C. difficile in colorectal cancer tumorigenesis. This work was borne out of the Vanderbilt Epithelial Biology Center and its NCI-funded Colon Molecular Atlas Project (ColonMAP). Their work shows that C. difficile is a component of pro-tumorigenic mucosal biofilms found directly overlaying human colorectal tumors. Furthermore, in genetically susceptible mouse models, toxigenic C. difficile strains accelerate tumorigenesis. Using high-dimensional, multi-omic approaches, their work provides insight into the emerging importance of the gut microbiota in colorectal cancer and potentially early-onset disease.

Lizandra Jimenez, PhD.
Dr. Jimenez working in the Weaver lab, carries out exciting research examining extracellular vesicle (EV)-carried miRNAs which have been shown to influence gene expression and functional phenotypes in recipient cells. Many investigators have found Ago2 in EVs, and it is postulated that Ago2 is a major transporter of miRNAs into small EVs (SEVs), such as exosomes. Others have reported extracellular Ago2 that is non-vesicular. She set out to evaluate the effect of growth factor signaling and serum contamination on the detection of Ago2 in SEVs. Wildtype KRAS colorectal cancer cells, DKs8, were conditioned with three different culture media (serum-free DMEM, EV-depleted FBS in DMEM, and Opti-MEM). Ago2 was detected in the same fractions as SEVs in both the serum-free DMEM and Opti-MEM conditions. In contrast, Ago2 was present in both vesicular and non-vesicular fractions in the EV-depleted FBS in DMEM condition. Analysis of SEVs by dot blot showed Ago2 primarily on the inside of SEVs. In a RNase A sensitive assay, she detected select miRNAs inside serum-free DMEM and Opti-MEM SEVs. In contrast, the miRNAs appear to be outside EV-depleted FBS in DMEM SEVs. Since Opti-MEM contains growth factors, she also collected SEVs from DKs8 cells conditioned with serum-free DMEM supplemented with EGF. She did not observe that Ago2 levels in the serum-free DMEM with EGF were altered compared to the serum-free DMEM condition. In summary, multiple factors may affect the ability to detect vesicular Ago2, including serum that may provide a source of extravascular Ago2 and also regulate the trafficking of Ago2 into vesicles.

Jennifer M Pilat, BA, IGP Student (Williams Lab)
Jennifer studies selenoprotein P (SELENOP) in the gastrointestinal tract, specifically SELENOP’s uptake mechanisms and signaling effects. SELENOP uptake occurs through known lipoprotein receptor-related proteins (LRPs) in different tissues, LRP1, LRP2, and LRP8, although the gastrointestinal SELENOP receptor remains unknown. LRP5 and LRP6 serve as ligand co-receptors in WNT signaling, of paramount importance to intestinal homeostasis and colorectal cancer (CRC). Over 90% of CRCs exhibit WNT hyperactivation. Jennifer recently discovered a novel interaction between SELENOP and LRP6, which she mapped to a specific region on SELENOP.
Moreover, SELENOP further augmented WNT-induced transcriptional activity in noncancer and CRC cell lines. Jennifer is now researching the mechanism by which WNT and SELENOP synergize to promote transcription of WNT target genes. In her free time, Jennifer loves hiking and reading.

 

Wendy Bindeman, BA an Demond Williams, BS
(Fingleton Lab)

Wendy and Demond are investigating the role of type II IL4 receptor in triple-negative breast cancer brain metastasis in the Fingleton lab. Breast cancer is the second-leading cause of brain metastasis. The cytokines IL4 and IL13 are overexpressed by many human solid tumors. Both are associated with invasive and metastatic phenotypes; IL13 is additionally consequential in primary brain tumors. These cytokines signal through type I (IL4 only) and type II (IL4/IL13) IL4 receptors. Importantly, expression of type II IL4R correlates with poor patient prognosis in basal-like (i.e., triple-negative; TNBC) breast cancer. They have shown that genetic loss of IL4R signaling in tumor cells attenuates lung and liver metastasis in mice. Additionally, they recently identified a role for IL4R signaling in modulating glycosylation in tumor cells. They hypothesize that IL4R signaling influences TNBC brain metastasis at least in part via modulating glycosylation. In a pilot mouse study, pharmacological blockade of IL4R after intracardiac injection of syngeneic TNBC cells resulted in some attenuation of metastatic brain growth and circulating tumor cell burden. They have also observed significant changes in the expression of a sialyltransferase (ST8SIA1) implicated in primary brain tumors and the abundance of several sialic acid-containing protein species in breast cancer cells following treatment with IL4 or IL13. Overall, thier data suggest that IL4R blockade may reduce TNBC brain metastasis, and IL4/IL13 can influence glycosylation in breast cancer cells. Future directions include evaluating the effect of IL4R blockade in combination with chemotherapy in mouse models of brain metastasis and further studies on the functional consequences of altered protein glycosylation after cytokine stimulation.
Wendy recently published an article entitled, “Glycosylation as a regulator of site-specific metastasis,” in Cancer Metastasis Rev. Read the article here.