Jason Weber
Washington University in St Louis, MO·Biochemistry
Triple-negative breast cancer (TNBC) lacks the three receptors that most breast cancer drugs target: the estrogen receptor, the progesterone receptor and HER2. It is aggressive, often comes back after treatment and has a worse outlook than other subtypes.
- Fields
Biochemistry
Medicine & Clinical Research
Microbiology & Immunology
- Topics
triple-negative breast cancer
RNA editing
ARF tumor suppressor
- Grants
- 3 known grants, through Jun 2028
What they work on
- Test whether the ARF tumor suppressor traps the RNA-editing enzyme ADAR1 in the nucleolus, a compartment inside the nucleus. This trapping would stop ADAR1 from holding back type I interferon alarm signaling in TNBC cells that lack working p53.
- Test whether turning on interferon signaling, using pathway activators or synthetic ARF-mimicking peptides, combined with removing ADAR1, kills triple-negative breast cancer cells in culture and in animal models.
- Determine whether overactivating interferon signaling by removing ADAR1 brings tumor-infiltrating lymphocytes into breast tumors, changes levels of the immune-blocking protein PD-L1, and triggers an immune response that prevents metastasis.
- Uncover how ADAR1 controls serine transport and production in TNBC cells, building on a screen of FDA-approved drugs that found ADAR1 loss makes cells sensitive to blocking the serine-making enzyme PHGDH.
- Test whether ADAR1-protected serine dependence can be targeted to slow tumor growth. The work uses mice with tumors implanted in mammary tissue, drug and diet treatments, combinations with one-carbon metabolism drugs, and PHGDH-inhibitor-resistant cancer cells.
- Through a multidisciplinary Breast Cancer Research Program, discover and validate personalized treatment targets, define mechanisms of progression and metastasis, and identify personal risk factors to reduce gaps in breast cancer deaths.
More about the research
Its main treatment problem is that there are few good drug targets. This research centers on ADAR1, an enzyme that edits RNA, the molecular messages copied from genes. Earlier work by the team found that TNBC cells depend heavily on ADAR1, which makes it a possible weak point. One project asks how ADAR1 holds back the cell's antiviral-style alarm system. A second asks how ADAR1 supports the cancer cell's supply of serine, an amino acid. A third grant supports a broader breast cancer research program that links basic, clinical and population science.
Why it matters
Patients with triple-negative breast cancer have few targeted treatment options. This work could point to new ones. It could support drugs that block ADAR1 or exploit its links to serine metabolism, alone or combined with interferon-pathway activators, PHGDH inhibitors or dietary changes. Such approaches may also help immune cells attack tumors. Beyond TNBC, the serine-metabolism findings could extend to other cancers that resist PHGDH inhibitors. The program grant's work on personal risk factors aims to reduce gaps in breast cancer deaths.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Ramesh Ganju
Ohio State University, OH·Microbiology & Immunology
Determine how S100A7 signaling controls genes that respond to interferon-gamma, especially PD-L1 and Fas, in African American TNBC cells and in engineered mice that overproduce mouse S100a7.
Shiaw-Yih Lin
University of Texas MD Anderson Cancer Center, TX·Medicine & Clinical Research
Test whether scarce DNA building blocks (dNTPs) cause RNA to be misinserted into TNBC genomes, and whether blocking RNase H2 leaves these errors in place, causing lethal replication stress. Also identify how tumors resist the inhibitor.
Jun He
Thomas Jefferson University, PA·Biochemistry
Determine how suppression of the microRNA miR-152 confers resistance to doxorubicin chemotherapy and radiation in triple-negative breast cancer cells, and test whether EZH2 and DNA hypermethylation are responsible for silencing miR-152.
The school
Washington University in St Louis: 97 labs on PI Pages, $1.2B a year on research, 365 research doctorates a year.
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