When I first started working on NCOR2 in Valerie Weaver’s laboratory at the University of California, San Francisco, this protein was already attracting attention as an epigenetic regulator of chemotherapy resistance in triple-negative breast cancer. Previous work from the lab had shown that NCOR2 helps tumor cells survive treatment. Yet treatment resistance alone did not seem sufficient to explain why patients with high NCOR2 expression consistently experienced worse outcomes.
This led us to a question: was NCOR2 doing more than helping tumor cells survive treatment? Could it also be helping tumor cells metastasize?
Because metastasis accounts for the vast majority of breast cancer-related deaths, understanding how disseminated tumor cells survive and eventually establish metastatic lesions remains one of the central challenges in cancer biology.
The first clues came from human samples. We compared tumors before and after chemotherapy as well as primary tumors and their matched metastatic lesions. What caught our attention was that nuclear NCOR2 was enriched in the most resilient tumor cell populations.
At that point, however, we still did not know whether NCOR2 was merely associated with metastasis or actively contributing to it.
What followed was a long series of experiments across multiple model systems. In addition to patient samples, we used in vitro models and syngeneic and transgenic mouse models. Each answer generated several new questions.
One observation kept standing out. NCOR2 had modest effects on primary tumor growth, yet its impact became striking once tumor cells had disseminated. Mice with reduced NCOR2 developed dramatically fewer metastatic lesions despite having primary tumors that appeared similar to those of control animals.
That observation changed how we thought about the project.
Instead of asking how NCOR2 influences tumor growth, we began asking how it influences the survival of disseminated tumor cells.
The answer gradually pointed toward the immune system.
As we analyzed metastatic lungs, we found marked changes in cell apoptosis and immune infiltration. Reducing NCOR2 led to an increase in CD8 T cells, suggesting that NCOR2 might be helping metastatic cells escape immune surveillance. The evidence became even stronger when the metastatic advantage provided by NCOR2 disappeared in severely immunodeficient mice.
At that point, we started to wonder whether immune evasion might be a central part of the story.
The final pieces of the puzzle emerged when we investigated antigen presentation. We discovered that NCOR2 suppresses the expression of genes involved in MHC class I antigen presentation, limiting the ability of CD8 T cells to recognize tumor cells. In effect, tumor cells with high NCOR2 become less visible to the immune system, allowing them to persist and eventually form metastatic lesions.
The key question was no longer whether NCOR2 promotes metastasis, but how it does so.
For me, one of the most rewarding aspects of this work was seeing different observations gradually coming together. Findings from patient samples, mouse models, and in vitro mechanistic studies all pointed in the same direction: NCOR2 emerged as an epigenetic regulator that coordinates treatment resistance, metastatic progression, and immune evasion.
Although our study identifies NCOR2 as a potential therapeutic target, many questions remain unanswered. What regulates NCOR2 during tumor progression? Does the same mechanism occur in other cancer types?
These questions remain for future work.
For now, it is exciting to share a story that began with a simple question about why NCOR2-high tumors behave so aggressively and ultimately revealed a previously unrecognized mechanism by which metastatic tumor cells escape immune surveillance.