Breast cancer metastasis to the brain: SIRPα’s two-part advantage

Breast cancer metastasis to the brain may gain two distinct advantages from the same molecule. SIRPα helps tumor cells remodel their own mitochondria while also changing the metastatic environment so that local immune cells in the brain become less responsive. The new study traced this mechanism across human tumor data, cultured cells and mouse models of triple-negative breast cancer.

SIRPα is already familiar to immunologists. It is usually studied on immune cells as part of a signaling system that can suppress immune activity. What was less clear was whether SIRPα produced by cancer cells themselves had a functional role.

Single-cell data from human breast cancers showed increased SIRPα expression in malignant epithelial cells from triple-negative tumors. Patient breast-to-brain metastatic lesions also showed increased SIRPα, and brain-tropic TNBC cells expressed more of the protein than their parental counterparts.

That raised a key question: was SIRPα merely a marker of aggressive cancer, or was it actively helping the cells metastasize?

First advantage: reshaping mitochondria

Changing SIRPα levels in tumor cells pointed to mitochondrial dynamics.

Mitochondria are not static cellular batteries. They continuously fuse and divide, and the balance between these states can influence energy production, stress responses, cell movement and other properties relevant to metastasis.

The researchers found that SIRPα promoted mitochondrial fission through a signaling pathway involving SHP2, ERK and Drp1. Drp1 is one of the core proteins that physically helps divide mitochondria into smaller units.

When SIRPα signaling was increased, mitochondria became more fragmented and the cancer cells acquired traits associated with greater metastatic capacity. In vivo, cancer-cell SIRPα overexpression significantly increased systemic metastasis.

But the effect did not stop inside the tumor cell.

Second advantage: making the brain more tolerant

A cancer cell that reaches the brain still has to survive in a new tissue. One of its challenges is microglia, the resident immune cells of the central nervous system.

Spatial protein profiling led the researchers to fibronectin, a component of the extracellular matrix that surrounds cells and can strongly influence how neighboring cells behave.

SIRPα signaling was associated with increased fibronectin. Fibronectin, in turn, pushed microglia toward a more tolerant state. Their inflammatory signaling and metabolic reprogramming were impaired, making it easier for cancer cells to escape local immune surveillance.

The same molecule therefore appeared to work on two fronts.

Inside the cancer cell, SIRPα activated the SHP2–ERK–Drp1 pathway, increased mitochondrial fission and promoted metastatic behavior. Outside the cancer cell, SIRPα-dependent changes in fibronectin helped create a microenvironment in which microglia responded less aggressively.

The researchers also tested what happened when the pathway was suppressed. In mouse metastasis models, inhibiting SIRPα reduced the number of metastatic lesions in the brain.

That finding is preclinical. The study did not test a SIRPα-directed therapy in patients, and it does not establish that blocking this pathway will prevent brain metastases or improve survival in people. The human data support the relevance of SIRPα to TNBC and brain metastatic tissue, whereas the causal experiments were performed largely in cells and animal models.

The work also broadens the way SIRPα is usually viewed. Most attention to this protein has focused on its role in immune cells. Here, the cancer cell itself appears to use SIRPα as part of its metastatic machinery.

One molecular signal may therefore help the tumor do two jobs at once: become better equipped to spread and make its destination less hostile when it arrives.