Extended Data Fig. 2: E-cad loss decreases migratory persistence ex vivo and increases invasion in vivo.

a, E-cad⁺ or E-cad⁻ cells from adeno-Cre-treated MMTV-PyMT; Cdh1^+/+ or Cdh1^fl/fl organoids, respectively, were manually tracked as they migrated within collagen I. Blue lines, cell tracks; circles, last tracked position of the cell at that time point. Scale bar, 50 μm. b, c, Disseminating E-cad⁻ cancer cells exhibit decreased migratory persistence (b) and displacement (c) relative to E-cad⁺ cells. Bar, median. ****P < 0.0001 and *P = 0.027 (Mann–Whitney test, two-sided). d, Adeno-Cre-transduced MMTV-PyMT; Cdh1^+/+ or Cdh1^fl/fl organoids were transplanted into cleared mammary fat pads of immunocompromised NSG mice. Tumour sizes were monitored twice weekly and collected after ~6–8 weeks. e, Tumours arising from Cdh1^fl/fl organoids were smaller than those arising from control organoids at the corresponding timepoint. Data are mean ± s.e.m. ****P < 0.0001 (regression analysis). f, Representative micrographs of primary tumours arising from Cdh1^+/+ or Cdh1^fl/fl donor tissue. Scale bar, 500 μm. Control tumours have relatively similar amounts of mT⁺ and mG⁺ cancer cells. By contrast, mG⁺ (Cre⁺E-cad⁻) cancer cells constitute <10% of Cdh1^fl/fl tumours. Data are mean ± s.e.m. ****P < 0.0001 (Kruskal–Wallis test). g, Left, representative tile scan of a primary tumour arising from control organoids (scale bar, 500 μm); an enlarged inset of the tumour–stroma border is shown (scale bar, 50 μm). Right, ~94% of the tumour border exhibits a pushing boundary. h, Left, representative tile scan of a mG⁺ (E-cad⁻) region of a primary tumour arising from Cdh1^fl/fl organoids (scale bar, 500 μm); enlarged insets of the tumour–stroma border are shown (scale bars, 50 μm and 20 μm). Right, more than 80% of the E-cad⁻ tumour edge has an invasive morphology.

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