Prof. Stephano Piccolo, PhD
University of Padua, Italy
3D blueprint of malignancies
Thursday, June 25th, 2026 – 11:00 am (CET)
https://tinyurl.com/SUNRiSEwebinarSPiccolo
Abstract
For decades, cell biology has advanced through a reductionist logic of extraordinary power, identifying genes, mutations, and signaling cascades that govern cellular behavior. Yet this success has encouraged a persistent simplification: the treatment of molecular events as primary units of causation, and of tissues as their aggregate output. The fundamental unit of physiology and disease is not the signaling web per se, but the cell in context — embedded in space, mechanically coupled to its neighbors, and continuously instructed by the architecture of the tissue it inhabits. This context includes the still mysterious 3D geometrical constraints and tissue-level processes underpinning malignant outgrowths.
We combined single-cell RNA sequencing, spatial transcriptomics, AI-supported 3D imaging and topology metrics 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) program that redeploys developmental branching morphogenesis to build metastases as a 3D trabecular lattice of epithelial cords. This morphogenetic capacity is not acquired at the metastatic site: MTM^HIGH cells pre-exist in primary tumors destined to metastasize, whereas non-metastatic primaries grow as compact, expansile masses. We identify the transcriptional regulators and stromal signaling that drive MTM — selectively required for metastatic outgrowth yet dispensable for primary tumor growth and initial dissemination — pointing to therapeutic vulnerabilities specific to the lethal macrometastatic stage.
More broadly, I will discuss how 3D outgrowth is a product of mechanobiology — the study of how physical forces shape cellular and tissue behavior. The field has moved from a specialized biophysical discipline to a foundational framework with implications across development, regeneration, aging, and disease.
