Reactivation of Fetal Morphogenesis Signals Predicts Breast Cancer Metastasis

Metastatic disease poses some of the most complex and lethal challenges in cancer treatment. For this reason, identifying therapeutic vulnerabilities of metastases remains an active area of investigation. Caire and colleagues set out to address this in the context of breast cancer (BC) by first characterizing the transcriptomes of human samples. In a comparative pseudobulk analysis of single-cell RNA sequencing data from 14 primary BCs and 10 metastases, genes involved in tube morphogenesis were found to be enriched in metastatic lesions. Given that normal mammary glands arise from branching tubulogenesis during development, the authors posited that metastases may aberrantly reactivate such programs to support outgrowth. In line with this hypothesis, 3D reconstructions of human BC metastases revealed a branched, lattice-like, trabecular structure. Importantly, while this architecture was consistent regardless of hormone receptor status or metastatic site in BC samples, metastatic sarcoma models did not exhibit a trabecular meshwork in those same sites (brain, lung). Combined with the transcriptomic analyses, these results suggested that reactivation of branching morphogenic developmental programs may be a tumor-intrinsic feature of BC metastases. The authors next devised a metastatic trabecular morphogenesis (MTM) signature containing fetal mammary morphogenesis genes specifically enriched in metastases. In a publicly available BC dataset, MTM expression in primary tumors was prognostic, where high levels of signature genes correlated with increased metastatic risk. To better understand drivers of MTM expression, layered epigenetic analyses were conducted using three human BC metastases, revealing that ETV transcription factor binding motifs were highly overrepresented upstream of MTM genes. Knockout of the most relevant ETV genes (ETV1/4/5) in human and mouse BC cell lines not only led to decreased expression of MTM genes but also reduced 3D branching in vitro and decreased macrometastatic outgrowth in vivo. A key component of the MTM signature is fibroblast growth factor (FGF) signaling, known to regulate branching morphogenesis during development. Much like ETV knockout models, both genetic and pharmacologic inhibition of FGFR were sufficient to reduce macrometastatic expansion in vivo. Taken together, this study suggests that a subfamily of ETVs act as master transcription factors that regulate MTM signature gene expression, drive 3D structural remodeling, and promote metastatic outgrowth that can be targeted by FGFR inhibition.Caire R, Bordo R, Zanconato F, Panciera T, Audoux E, Contessotto P, et al. A 3D morphogenetic blueprint for metastatic outgrowth in breast cancer. Cell 2026 March 31 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.