The projects featured below are the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC)’s current funding recipients.
2025
John Maciejowski (Classic Individual)
Investigating A3A-Induced Transcriptional Reprogramming in Metastasis
The enzyme APOBEC3A (A3A) is well-known for its role in causing DNA mutations that fuel cancer’s evolution. However, its full impact on cancer progression, particularly its role in metastasis remains unclear. Our research has uncovered a surprising, non-mutagenic function for A3A. We found that A3A is expressed in brief, intense bursts within individual cancer cells. These bursts act like a switch, reprogramming the cells’ identity. They transition from their original state to a more resilient “injury-response” or “squamous” state, a transformation known as lineage plasticity. This cellular reprogramming is strongly associated with metastasis and poor patient outcomes, but the underlying mechanisms have been a mystery. This project is built on the central hypothesis that these A3A-driven bursts of activity give cancer cells the flexibility to survive and form metastases. This grant will support two primary aims. First, we will investigate the molecular machinery behind this reprogramming. We will explore how the bursts of A3A activity trigger DNA damage signals that, in turn, activate the genes responsible for this dangerous squamous state. Second, we will determine the direct consequences of this process on metastasis. Using advanced lineage tracing techniques in colorectal and breast cancer models, we will track the descendants of cells that experience A3A bursts to confirm if they are the primary source of metastatic tumors. We will also test whether A3A is essential for this cellular switch and subsequent metastatic growth. Ultimately, this work challenges the conventional view of A3A as solely a DNA-mutating enzyme. Our findings aim to establish A3A as a dual-threat driver of cancer, capable of both editing the genome and reprogramming cell identity. Unraveling this novel mechanism could provide critical new insights into the drivers of metastasis and uncover new therapeutic vulnerabilities to treat advanced cancers.
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.