A 3D morphogenetic blueprint for metastatic outgrowth in breast cancer.

Caire R; Bordo R; Zanconato F; Panciera T; Audoux E; Contessotto P; Fakiola M; Bason R; Romano O; Suli A; Battilana G; Marchionni M; Forcato M; Donzelli S; Dieci MV; Griguolo G; Carosi M; Fassan M; Guzzardo V; Dei Tos AP; Marsoni S; Wu PH; Wirtz D; He S; Casali C; Volpin F; Blandino G; Tripodo C; Bicciato S; Guarneri V; Pagani M; Cordenonsi M; Piccolo S

doi:10.1016/j.cell.2026.03.009

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A 3D morphogenetic blueprint for metastatic outgrowth in breast cancer.

Cell 2026

Caire R, Bordo R, Zanconato F, Panciera T, Audoux E, Contessotto P, Fakiola M, Bason R, Romano O, Suli A, Battilana G, Marchionni M, Forcato M, Donzelli S, Dieci MV, Griguolo G, Carosi M, Fassan M, Guzzardo V, Dei Tos AP, Marsoni S, Wu PH, Wirtz D, He S, Casali C, Volpin F, Blandino G, Tripodo C, Bicciato S, Guarneri V, Pagani M, Cordenonsi M, Piccolo S

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The tissue-level processes underpinning metastatic outgrowth remain unclear.

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APA Caire R, Bordo R, et al. (2026). A 3D morphogenetic blueprint for metastatic outgrowth in breast cancer.. Cell. https://doi.org/10.1016/j.cell.2026.03.009

MLA Caire R, et al.. "A 3D morphogenetic blueprint for metastatic outgrowth in breast cancer.." Cell, 2026.

PMID 41923644

DOI 10.1016/j.cell.2026.03.009

Abstract

The tissue-level processes underpinning metastatic outgrowth remain unclear. We combined single-cell RNA sequencing, spatial transcriptomics, and AI-supported 3D imaging in human breast cancer with functional investigations in mice to uncover a 3D morphogenetic process essential for macrometastatic expansion. Macrometastases pervasively activate a metastatic trabecular morphogenesis (MTM) gene-expression program that redeploys developmental branching morphogenesis to build macrometastases as a 3D trabecular lattice of epithelial cords. MTM cells pre-exist in primary tumors destined to metastasize, whereas MTM primaries are non-metastatic and display a compact, expansile growth architecture. Chromatin immunoprecipitation sequencing (ChIP-seq) on metastatic organoids identifies ETV1/4/5 as master regulators of MTM and branching cancer morphogenesis, required for metastatic outgrowth but dispensable for primary tumor take, bulk growth, and initial metastatic dissemination. Spatial and functional analyses reveal stromal fibroblast growth factor (FGF)→fibroblast growth factor receptor (FGFR) signaling as an actionable MTM dependency. Thus, we link metastatic outgrowth to a 3D developmental morphogenetic process, exposing therapeutic vulnerabilities specific to the lethal macrometastatic stage.