The projects featured below are the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC)’s current funding recipients.
2024
Ming Li (Classic Individual)
Reprogramming DNA Clearance to Drive Cancer Cell Senescence and Tumor Suppression
The tumor tissue ecosystem is characterized by high cancer cell turnover associated with enhanced cell proliferation and death. Efficient clearance of damage-associated molecular patterns (DAMPs), such as the nuclear or mitochondrial DNA released from stressed or dying cancer cells, may promote cancer cell escape from host immune defense responses. Following up our previous findings that tumor-associated macrophages express high levels of DNASE1L3, an extracellular DNASE that effectively degrades membrane-encapsulated and nucleosome-bound DNA, we generated a DNASE1L3-deficint mouse strain and evaluated its function in a transgenic breast cancer model. We found that DNASE1L3 deficiency did not affect tumor growth but triggered production of autoantibodies that could function as an alternative DNA clearance mechanism. Indeed, genetic or pharmacological depletion of B cells synergized with DNASE1L3 deletion to inhibit tumor development in association with induction of cancer cell senescence. In a cancer cell co-culture system, cell senescence was readily triggered by apoptotic cell bodies, which was independent of the cytosolic DNA sensor cGAS, but dependent on the endosomal DNA sensor TLR9 that activated, among other inflammatory signaling pathways, the EIF2a-mediated integrated stress response. Notably, high TLR9 or p-EIF2a expression tracks with favorable prognosis in TNBC patients. Based on these findings, we hypothesize that multilayered extracellular DNA scavenging pathways operate in the tumor tissue with DNASE1L3- and autoantibody-assisted DNA clearance preventing cancer cell uptake of immunostimulatory DNA and the TLR9-mediated cancer cell senescence as a novel innate immune anti-tumor response. In this proposal, we will test this hypothesis by defining how uptake of uncleared extracellular DNA drives cancer cell senescence and investigate whether DNA clearance pathways can be targeted for cancer therapy.
2023
Ross Levine (Classic Individual)
Clonal hematopoiesis as a driver of metastatic relapse in early breast cancer
Efforts to identify genomic biomarkers to predict breast cancer outcomes have traditionally focused on tumor intrinsic factors; thus, identification of tumor extrinsic factors with prognostic and therapeutic importance is imperative to better predict patient outcomes and redefine therapeutic strategies for the prevention and treatment of metastatic breast cancer. Genomic sequencing studies have uncovered that 25% of breast cancer patients, carry somatic mutations in their leukocytes, a condition known as clonal hematopoiesis (CH). The incidence of CH increases with aging and has been recognized as a major risk factor for the development of subsequent hematologic malignancies and cardiovascular disease. CH mutations frequently occur in genes involved in myeloid malignancies, most commonly in the epigenetic modifier DNMT3A. A hallmark of breast cancer is the admixture of tumor cells and myeloid cells, which play a key role in determining therapeutic resistance and metastasis through the fine tuning of inflammatory signals. More recently, we have revealed that CH mutations are enriched in breast cancer tumor infiltrating leukocytes and that CH in putative cancer drivers (CH-PD) is associated with increased risk of solid tumor dependent morbidity and mortality. Although the most common cause of death in these patients was metastatic disease progression, the mechanisms by which CH contributes to therapeutic resistance and metastatic relapse remain unclear. Our central hypothesis is that CH alters the inflammatory responses of myeloid cells to drive therapeutic resistance and metastatic relapse via increased proliferation of disseminated cancer cells. This project will A) Determine why breast cancer cells re-emerge as metastasis by exploring the effects of CH-PD on the metastatic outcomes of patients with early breast cancer; and B) Determine how to prevent lethal metastatic recurrences by targeting inflammatory signals in mouse models of CH and breast cancer metastasis. This study represents an innovation because (1) the biological processes behind how aging and CH contribute to metastatic progression remains largely unexplored, and (2) understanding how CH mutant leukocytes contribute to the pro-metastatic process may provide a new tool to identify patients at highest risk of metastatic relapse and lead to the identification of actionable targets to limit tumor promoting inflammation and metastasis.