CURRENT LAB PROJECTS

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Triple-negative breast cancer (TNBC) has remained a considerable clinical challenge due to the lack of efficacious genetic targets. We need unique effective therapies and accurate biomarkers that can be used to predict patient responses in TNBC. We find that the ARF tumor suppressor is lost alongside p53 mutation in 60% of TNBC. Potentially stemming from the dual loss of ARF and p53, we have observed that type I IFN signaling is elevated in TNBC. We show that this IFN production is being kept in check by the ADAR1 enzyme. Notably, we discovered that ADAR1 is a novel binding partner for ARF. The central premise of this project is that the novel ARF-ADAR1 interaction provides key insights into how these two proteins function in the etiology of TNBC. The research project focuses on the role of this interaction in regulating the type I interferon response and sensitizing TNBC cells to cell death and immune recognition. The overarching hypothesis of the proposed research is that loss of ARF and p53 results in elevated type I IFN signaling and sensitizes cells to ADAR1 depletion.

Collaborators: Dr. Cynthia Ma (WashU), Shunqiang Li (WashU), Alana Welms (Utah), Brenda Bass (Utah), Rachel Schiff (Baylor), Carmine De Angelis (Naples)

Regional lymph nodes are the primary sites of lymphatic drainage from all areas of the breast, and the extent of their involvement in breast cancer is a strong predictor of disease relapse and patient survival. Recent studies demonstrate that lymphatic vessels undergo dynamic remodeling when co-cultured with tumor cells, which facilitates metastasis. Lymphatic vessel contribution has not yet been evaluated for any racial bias in TNBC. Although much has been learned about the distinct mutational landscape of TNBC tumor cells, the underlying molecular and cell biological mechanisms that drive the apparent racial disparity remain unknown. Currently, a major obstacle in the field is that accurate models of racially diverse TNBC and its lymphatic microenvironment do not exist, underscoring the overall difficulty in identifying drivers of aggressive African American disease. In this project, we will develop a series of innovative TNBC-on-a-chip microfluidic devices in which to study potential racial drivers of TNBC phenotypes using patient-derived tumor xenografts and patient-derived lymphatic endothelial cells.

Collaborators: Greg Longmore (WashU) and Steven George (UC-Irvine)

As the most well-studied RNA editing enzyme, adenosine deaminase acting on RNA 1 (ADAR1) can drive transcriptomic and proteomic diversity through A(adenosine)-to-I(inosine) RNA editing in human diseases, including cancer. We recently demonstrated an elevated ADAR1-dependent phenotype shared by TNBC, highlighting its potential as a novel therapeutic target. Through RNA sequencing, we identified significant MDM2 upregulation among all cell lines (TNBC and non-TNBC) upon ADAR1 loss. It has recently been shown that MDM2 plays paradoxical roles in cancer, acting as either a therapeutic target with pro-tumorigenic activities, or a tumor-suppressive factor by promoting lipid remodeling and iron-dependent cell death (ferroptosis). We hypothesize that ADAR1 loss in breast can sensitize cancer cells to 1) ferroptosis through induced lipid remodeling, or 2) MDM2 inhibitory treatments through MDM2 upregulation, dictated by their subtypes.

Collaborators: Gary Patti (WashU)

While much of the NF1 scientific community is focused on the mTOR pathway as a sole manifestation of NF1, our group has chosen to study the mechanisms underlying the progression from PN to MPNST through the concomitant loss of both the Nf1 and Arf tumor suppressors. We have shown that this progression involves an increase in mRNA translation. The goal of this project is to identify the mRNAs whose translation is affected by the loss of Nf1 and Arf, and to characterize the mechanism behind their altered translation. To achieve this goal, we are using two complimentary approaches. The first involves a novel screen, one that has never been performed in the Neurofibromatosis field, although our lab has already utilized this technique in other cell types. Our screen will serve to identify mRNAs that are either loaded faster, slower or not at all on ribosomes in Nf1/Arf-deficient Schwann cells. The second approach involves understanding how these mRNAs are loaded differently by identifying proteins that uniquely interact with these mRNA. If we can identify these translation regulators, then we may discover why PNs progress to MPNST following loss of Nf1 and Arf tumor suppressor genes. 

Collaborators: Angela Hirbe (WashU) and David Gutmann (WashU)