Macrophages in ovarian cancer can reshape a barrier to invasion

Macrophages in ovarian cancer may do more than respond to a tumor: they can alter the tissue the cancer is trying to enter. In the new study, pro-inflammatory macrophages isolated from omental metastases released signals that pushed mesothelial cells into a more mobile, contractile state. In a laboratory model, ovarian cancer cells crossed the remodeled mesothelial layer more readily.

The mesothelium is a thin sheet of cells lining the abdominal cavity and covering internal organs. Ovarian cancer often spreads across this cavity, including through ascitic fluid, rather than relying only on the bloodstream. Tumor cells can then attach to the peritoneum and the omentum. Before invading the tissue underneath, they have to interact with the mesothelial layer that normally helps form a protective surface.

Macrophages changed with location

The researchers compared tumor-associated macrophages from two sites in patients with high-grade ovarian cancer: ascites and omental metastases. For single-cell RNA sequencing, they analyzed matched samples from three untreated patients, yielding 10,506 macrophages after filtering.

The two compartments looked strikingly different. Ascites macrophages were enriched for features traditionally associated with an M2-like state. Macrophages from omental metastases, by contrast, more often showed a mixed profile containing both M1- and M2-associated features.

That matters because the familiar shorthand — M1 as anti-tumor and M2 as pro-tumor — did not describe these cells well. The macrophages in metastases carried clear inflammatory features, yet their gene-expression programs also pointed toward tissue remodeling.

The team then asked whether those differences had a functional consequence. They collected conditioned medium — the mixture of molecules released by macrophages — and applied it to primary human mesothelial cells. In experiments using matched ascites- and omentum-derived macrophages from five patients, medium from the omental macrophages produced the stronger remodeling response.

Mesothelial cells lost some epithelial characteristics, became elongated and fibroblast-like, and became more contractile. This process is known as mesothelial-to-mesenchymal transition. In practical terms, cells that normally contribute to a continuous surface shift toward a state that is better suited for remodeling tissue and less suited to maintaining a tight barrier.

A separate invasion assay added a functional readout. After mesothelial cells had been exposed to factors released by pro-inflammatory macrophages, ovarian cancer cells crossed the mesothelial layer and entered a collagen matrix more efficiently. This was an in-vitro experiment, so it does not establish that the same sequence drives metastasis in patients. But it connects mesothelial reprogramming to a behavior directly relevant to tumor dissemination.

IL-1α emerged as a key trigger

The next question was which macrophage-derived factor was responsible. Proteomic profiling identified dozens of proteins elevated in the pro-inflammatory macrophage secretome. Several inflammatory cytokines could produce part of the mesothelial response, but interleukin-1 alpha, or IL-1α, stood out.

Neutralizing IL-1α weakened the change in mesothelial-cell shape, reduced mesenchymal gene expression, and decreased collagen contraction. Neutralizing IL-1β or TNFα did not produce the same effect. In a separate proteomic analysis of matched ascites and omental macrophages from six patients, IL-1α was again enriched in macrophages from the omental metastases.

IL-1α was not acting alone. It increased production of TGFβ by the mesothelial cells themselves and also increased expression of TGFBR1, the receptor that makes those cells responsive to TGFβ. The result was a reinforcing loop: a macrophage-derived inflammatory signal prompted the mesothelial cell to make more TGFβ while becoming more sensitive to that same pathway. IL-1α also activated ERK and p38 MAPK signaling in parallel.

The interaction between the two signals was particularly revealing. IL-1α or TGFβ alone did not fully reproduce the macrophage-induced phenotype. Together, they generated a much more complete mesenchymal transition and increased contractility. Blocking both pathways at the same time largely abolished the remodeling response in the cell system.

An immune cell can help prepare the landing site

The human data supported the laboratory model, although on a limited scale. IL1A expression was concentrated mainly in macrophage clusters from omental metastases, and immunohistochemistry showed CD68-positive, IL-1α-positive macrophages next to a micrometastatic lesion in a clinical specimen. The authors also reanalyzed an independent single-cell dataset of patient-derived mesothelial cells and found populations with overlapping mesenchymal and IL-1-response features.

The main limitation is therefore one of scale and biological context. The patient cohorts were small, and the causal mechanism was tested primarily in cultured cells. The study did not show that blocking IL-1α reduces ovarian cancer metastasis in animals or patients, nor did it establish prognostic value. Previous clinical studies of IL-1α blockade in advanced cancers have also failed to demonstrate clear conventional anti-tumor activity.

The result is more compelling as a change in the picture of metastasis than as a treatment claim. A disseminating cancer cell may encounter a barrier that has already been altered by neighboring immune cells. In this study, IL-1α provided part of that link: a macrophage signal that induced mesothelial cells to change their own state, making the local tissue more permissive to invasion.