Splicing Factor SRSF7 Emerges as a Master Switch Behind Triple-Negative Breast Cancer Spread

Triple-negative breast cancer remains one of the most feared diagnoses in oncology. Lacking the estrogen receptor, the progesterone receptor, and HER2, it offers clinicians none of the molecular handles that make other breast cancer subtypes treatable with targeted therapies, and its tendency to metastasize aggressively makes it the deadliest form of breast cancer. Now, a team of researchers at Leiden University and Erasmus MC in the Netherlands has uncovered an unexpected driver of that lethal spread: a single RNA splicing factor called SRSF7, which appears to orchestrate an entire gene-expression program that enables cancer cells to migrate, invade, and colonize the lungs. The study, published in the Journal of Experimental & Clinical Cancer Research, positions RNA splicing not as cellular housekeeping but as an active, druggable vulnerability in metastatic disease.

Splicing is the process by which the cell’s molecular machinery cuts out non-coding introns from freshly transcribed messenger RNA and stitches the remaining exons together. Far from being a uniform operation, splicing can be regulated so that the same gene yields multiple protein variants depending on which exons are retained or skipped. This alternative splicing is executed by the spliceosome, a massive ribonucleoprotein complex assembled from hundreds of components, including small nuclear ribonucleoproteins and a family of serine-arginine rich proteins known as SR proteins. Cancer cells frequently hijack this machinery, producing splice variants that favor uncontrolled growth, survival under stress, or, as the new study shows, the physical ability to move through tissue.

To find out which splicing factors actually matter for metastatic behavior, the Leiden-led team, spearheaded by first authors Nasi Liu, Jurjun J. S. van der Velde, and Esmee Koedoot under the senior guidance of Sylvia E. Le Dévédec and Bob van de Water, ran a systematic functional screen. Using an imaging-based RNA interference approach, they knocked down each of 244 spliceosome components in two highly motile triple-negative breast cancer cell lines, MDA-MB-231 and Hs578T. Rather than measuring proliferation or viability, the researchers focused on motility itself, deploying phagokinetic track assays, in which cells leave trails as they move across a coated surface, alongside random cell migration assays tracked by high-content microscopy. This design allowed them to quantify migration speed, track geometry, and net displacement for thousands of perturbations in parallel.

The screen’s most striking finding was selectivity. While some spliceosome components, when depleted, broadly impaired cell proliferation or triggered cell death, a distinct subset of splicing factors specifically curtailed cell motility without substantially compromising growth or survival. Among these, SRSF7 stood out as a central regulator. The team confirmed the result with multiple independent methods: siRNA-mediated knockdown, validated at the protein level by western blotting, and inducible CRISPR-Cas9 knockout, in which Cas9 activity and guide RNA expression are switched on with doxycycline. Both approaches converged on the same conclusion: removing SRSF7 sharply reduces the migratory and invasive capacity of triple-negative breast cancer cells in culture.

Crucially, the phenomenon held up in living animals. The researchers used a tail-vein metastasis model, injecting luciferase-labeled cancer cells into mice and tracking lung colonization over time with longitudinal bioluminescent imaging. When SRSF7 was knocked out in the inducible knockout lines, metastatic burden in the lungs dropped dramatically, as confirmed by lung weight measurements and by ink perfusion-based quantification of macrometastases. Notably, the team also examined primary tumor growth in an orthotopic model and found that SRSF7 loss did not simply eliminate the tumor cells; the effect was most pronounced on the cells’ ability to seed and expand metastatic colonies. That distinction matters therapeutically, because a target that specifically disables dissemination could complement existing treatments that shrink primary tumors.

What is SRSF7 actually doing at the molecular level? To answer this, the researchers turned to next-generation RNA sequencing, generating deep transcriptomic datasets from SRSF7-depleted cells in both cell lines and from two independent CRISPR knockout clones. Differential gene-expression analysis revealed that SRSF7 loss broadly downregulates a coordinated program of genes involved in extracellular matrix organization, cell-matrix adhesion, integrin signaling, and cytoskeletal regulation. In other words, SRSF7 does not merely tweak a single migration gene; it maintains the molecular infrastructure that allows a cancer cell to grip the matrix, remodel its surroundings, and propel itself forward. Pathway enrichment analyses using Reactome and KEGG databases confirmed the coherence of this program across cell lines and across knockdown and knockout modalities.

The sequencing data went further, cataloguing thousands of SRSF7-dependent alternative splicing events. Among these, recurrent exon-skipping alterations stood out, affecting genes with established roles in migratory and adhesive phenotypes. The researchers quantified these events using the percentage-spliced-in metric, comparing inclusion levels between control and SRSF7-depleted conditions, and found strong concordance between the two independent knockout clones. They also observed that SRSF7 knockout reduced the inclusion of a poison cassette exon within the SRSF7 locus itself, a self-regulatory feedback element in which the retained exon introduces a premature stop codon that degrades the transcript. This autoregulatory loop suggests that cells may have an intrinsic mechanism for damping SRSF7 levels, one that metastatic cancer cells appear to override.

The clinical relevance of these findings was tested against patient data. By mining triple-negative breast cancer gene-expression cohorts, including data from The Cancer Genome Atlas, the team showed that elevated SRSF7 expression correlates with poorer survival outcomes, including measures of overall, disease-free, and metastasis-free survival. Candidate splicing factors identified in the screen, including SRSF7, were also expressed at higher levels in tumor tissue than in normal breast tissue, in triple-negative tumors compared with estrogen receptor-positive tumors, and in basal-like breast cancer cell lines compared with luminal lines. Expression of the candidates additionally increased with pathologic stage, tying the molecular biology of the screen directly to the trajectory of human disease.

The study also carries implications for how splicing-directed therapies might be developed. Broad spliceosome inhibitors, such as compounds that trap the U2 small nuclear ribonucleoprotein complex onto pre-messenger RNA, have shown activity in myelodysplastic syndromes and some solid tumors, but their toxicity profile reflects the fact that every cell needs splicing. The Leiden and Erasmus findings suggest a more refined strategy: because certain splicing factors like SRSF7 are selectively required for metastatic behavior rather than basic viability, tumors may harbor splicing-factor dependencies that can be exploited at doses or with modalities that spare normal tissue. The observation that SRSF7 depletion suppresses lung colonization while leaving proliferation largely intact in vitro hints at a therapeutic window, although translating that into a clinical intervention will require selective ways to inhibit or degrade SRSF7, a challenge the field of RNA-binding protein drug discovery is actively pursuing.

For now, the work delivers something triple-negative breast cancer research has long needed: a systematic, unbiased map of which parts of the splicing machinery actually drive metastasis, validated from cultured cells through animal models to patient cohorts. It reframes metastasis as a disease of information processing, in which the way RNA transcripts are assembled determines whether a tumor cell stays put or spreads. With the European Research Council and the Dutch Cancer Society supporting the program, and with the underlying datasets and models now published, the researchers and the wider field can begin testing whether targeting SRSF7 and its splicing network can turn one of cancer’s most lethal capabilities into its Achilles’ heel.

Subject of Research: The role of the RNA splicing factor SRSF7 in regulating metastatic programs in triple-negative breast cancer

Article Title: SRSF7 controls RNA splicing programs driving triple-negative breast cancer metastasis

Article References: Liu, N., van der Velde, J. J. S., Koedoot, E., Smid, M., de Weerd, V., Martens, J. W. M., Le Dévédec, S. E., & van de Water, B. (2026). SRSF7 controls RNA splicing programs driving triple-negative breast cancer metastasis. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03817-0

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03817-0

Keywords: triple-negative breast cancer, SRSF7, RNA splicing, splicing factor, metastasis, spliceosome, alternative splicing, cell migration, CRISPR-Cas9, extracellular matrix, integrin signaling, cancer genomics