The projects featured below are the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC)’s current funding recipients.
2026
Frederic Geissmann (Classic Individual)
Control of the tumor microenvironment by macrophage Nr1h3/LXRalpha
Macrophages are abundant components of most tumors and attractive targets in cancer immunotherapy because they can engulf live tumor cells, remodel the tumor microenvironment, and activate anti-tumor immune responses. However, in most tissues and tumors, macrophages fail to mount effective responses and often promote tumor growth, metastasis, and immunosuppression.
Unlike most other macrophages, liver-resident Kupffer cells (KCs) are highly phagocytic and restrict tumor growth. Previous work identified the lineage-determining transcription factor ID3 as a critical regulator of macrophage anti-tumor activity. Preliminary studies now indicate that another Kupffer cell-specific factor, LXRA, also promotes tumor-cell engulfment and anti-tumor immunity and may cooperate with ID3 to regulate a macrophage “anti-tumor” program.
This project will investigate how LXRA, independently and in cooperation with ID3, regulates Kupffer cell-mediated tumor control. It will also determine whether LXRA, alone or in combination with ID3, can reprogram tumor-supportive mouse and human macrophages toward an anti-tumor state. These studies may inform the development of macrophage-based cancer immunotherapies.
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.