Moruzzi M , Nestor-Bergmann A , Goddard GK , Tarannum N , Brennan K , Woolner S .

Wellcome Trust , 106506/Z/14/Z Wellcome Trust , 098390/Z/12/Z Wellcome Trust , Biotechnology and Biological Sciences Research Council

                carcinoma

Xla Wt + Hsa.kras{V12} : GFP (Fig. 1 J K)
Xla Wt + Hsa.kras{V12} : GFP (Fig. 3 A)
Xla Wt + Hsa.kras{V12} : GFP (Fig. 3 D G)
Xla Wt + Hsa.kras{V12} : GFP (Fig. 4 B)
Xla Wt + Hsa.kras{V12} : GFP (Fig. 4 F)
Xla Wt + Hsa.kras{V12} : GFP (Fig. S 1 E)
Xla Wt + Hsa.kras{V12} : GFP (Fig. S 1 F G)
Xla Wt + Hsa.kras{V12} : GFP (Fig. S 3 F G)
Xla Wt + Hsa.kras{V12} : GFP (Fig. S 4 A)
Xla Wt + Hsa.kras{V12} : GFP (Fig. S 4 D)
Xla Wt + Hsa.kras{V12} : GFP + myh10 MO (Fig. S 4 D)
Xla Wt + Hsa.kras{V12} : GFP + myh10 MO (Fig. S 4 F)
Xla Wt + Hsa.myc:GFP (Fig. 1 F)
Xla Wt + Hsa.myc:GFP (Fig. 3 A)
Xla Wt + Hsa.myc:GFP (Fig. S 1 I J)
Xla Wt + Hsa.rhoa{Q63L}:GFP (Fig. 4 C)
Xla Wt + Hsa.rhoa{Q63L}:GFP (Fig. 4 D)
Xla Wt + Hsa.rhoa{Q63L}:GFP (Fig. 4 E)
Xla Wt + Hsa.rhoa{Q63L}:GFP (Fig. S 4 C)
Xla Wt + myh10 MO (Fig. S 4 F)

	Graphical Abstract
	Figure 1. Modeling early-stage carcinoma in Xenopus laevis. (A) Schematic of the microinjection protocol. Xenopus embryos were injected with Cherry-histone-H2B and BFP-CAAX mRNA at the 2-cell stage. At the 32-cell stage, a single cell was injected with GFP, GFP-kRasV12, or GFP-cMYC mRNA. Embryos were developed to early gastrula stage 10 and imaged. (B–D) Confocal microscopy images of Xenopus embryos developed to early gastrula stage 10, following injection of a single cell at the 32-cell stage with (B) GFP, (C) GFP-kRasV12, or (D) GFP-cMYC mRNA. Scale bars represent 100 μm. (E) Western blot showing phosphorylated ERK, unphosphorylated ERK, and α-tubulin expression in uninjected control embryos and embryos injected with GFP, GFP-kRasV12, or GFP-cMYC mRNA. (F) Bar chart showing the average percentage of cells that divided per minute of time lapse, in either GFP, GFP-kRasV12, or GFP-cMYC overexpression clusters (∗p < 0.05; Kruskal-Wallis test: n = 7 GFP, 8 GFP-kRasV12, and 9 GFP-cMYC embryos). Also displayed is the proportion of cell divisions that occurred out of the epithelial plane (shaded portion of the bar). Error bars show SEM. (G) Stills from a confocal microscopy time lapse of a representative embryo with a GFP-kRasV12 cell cluster at stage 10. White arrows highlight cells observed to be lost basally over the course of the time lapse. (H) Dot plot showing average percentage of cells that extruded basally from GFP, GFP-kRasV12, or GFP-cMYC cell clusters (∗p < 0.05; Kruskal-Wallis test: n = 7 GFP, 9 GFP-kRasV12, and 5 GFP-cMYC embryos). Error bars are SEM. (I and J) Microscopy images of representative embryos at stage 38 that had a (I) GFP- or (J) GFP-kRasV12-expressing cluster at stage 10. Arrow indicates an induced tumor-like structure (ITLS). Anterior is toward the left; scale bars represent 500 μm. (K) Quantification of ITLS formation at stage 38 in embryos that had GFP or GFP-kRasV12 clusters at stage 10 (∗∗p < 0.01; Mann-Whitney test; n = 5 independent experiments; a total of 120 GFP and 97 GFP-kRasV12 embryos were assessed). Error bars are SEM. See also Figure S1 and Videos S1 and S2.
	Figure S1: Further Characterisation of Oncogene-Expressing Cell Clusters in Xenopus laevis. Related to Figure 1. (A) Bar chart shows the average percentage of embryos, injected at the 32-cell stage, alive at stage 10. Error bars show SEM. (B) Bar chart shows the average percentage of surviving stage 10 embryos, injected at the 32-cell stage, that have a GFP-positive cluster in the superficial animal cap layer (*p<0.05, Kruskal-Wallis test, n=3 clutches of embryos). Error bars show SEM. (C) Western blots (left) and associated quantification (right), showing phosphorylated ERK (pERK), ERK and α-tubulin expression in embryos injected with GFP or GFP-kRasV12. For quantification, pERK and ERK levels were normalised against α-tubulin and shown as a fold change (*p<0.05, Student t-test, n=3 independent experiments). Error bars show SEM. (D) Classification of in-plane and out of plane divisions for data in Figure 1F. Divisions in GFP-kRasV12 (green) cells were identified in time-lapse videos by condensed chromosomes at the metaphase plate (arrows) using Cherry-H2B (red and single greyscale channel) and followed through to cytokinesis. If two nuclei could be seen separating and resolving in two cells in the epithelium the division was classified as “in-plane”; if only one nucleus resolved the division was classified as “out of plane” (nuclei following cytokinesis are marked with a red asterisk). (E) Stills from a representative confocal time-lapse of a Xenopus embryo at early gastrula stage 10, with a GFP-kRasV12 cell cluster in the superficial animal cap layer (Video S1). No apical extrusion or apoptosis was observed in either the GFP-kRasV12 clusters or the surrounding wild-type cells. (F) Confocal image shows an embryo, where GFP- kRasV12 mRNA was injected into a single cell at the 32-cell stage, that was fixed at stage 10, bisected and immunostained for GFP (green). (G) Confocal image shows an embryo, where GFP-kRasV12 mRNA was injected into a single cell at the 32-cell stage, that was fixed at stage 10, cryosectioned and immunostained for GFP (green), tubulin (red) and DAPI (blue). Arrows highlight cells that have lost cell-cell junctions and are no longer attached to the animal cap. (H) Stills from a representative confocal microscopy time-lapse of a Xenopus embryo at early gastrula stage 10, with a GFP-cMYC cell cluster in the superficial animal cap layer (Video S2). No apical extrusion or apoptosis was observed in either the GFP-cMYC clusters or the surrounding wild-type cells. (I) Immunofluorescence of cleaved caspase-3 (red; nuclei in blue) in GFP and GFP-cMYC injected embryos. Images of superficial and deep layers of the same stage 10 embryo are shown, cells positive for cleaved caspase-3, a marker of apoptosis, are found in the deep layer of GFP-cMYC injected embryos. (J) Quantification of cleaved caspase positive cells in GFP, GFP-kRasV12 or GFP-cMYC injected embryos (p<0.01, Kruskal-Wallis test, n=5 embryos). (K) Microscopy images show a representative embryo at stage 10 and stage 38 that was co-injected with GFP-cMYC and mCherry mRNA at the 32-cell stage. Anterior is towards the right. Scale bars represent 20 μm in D and I, 50 μm in F ,100μm in E, G, H and K (Stage 10), and 500μm in K (Stage 38).
	Figure 2. kRasV12 cell cluster imposes a mechanical strain on the wild-type epithelium(A and B) Cropped regions of confocal time-lapse stills showing laser ablation at a cell edge (highlighted by cherry-UtrCH: F-actin) in a GFP-kRasV12 cluster (A) and a surrounding wild-type cell (B). Ablation occurs at t = 0, yellow lines show the original positions of cell vertices before laser ablation, and red lines show the real-time positions of cell vertices.(C) Recoil measurements for cells in GFP-control (red), GFP-kRasV12 (green), and GFP-cMYC (yellow) clusters and areas of wild-type tissue around GFP-kRasV12 clusters (wild type; light green); n = 10 cells for each sample; error bars are SEM.(D) Initial recoil velocity calculated from recoil measurements in (C); one-way ANOVA: ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001; n = 10 cells for each sample; error bars are SEM.(E) Simulated tissue, randomly generated, starting under conditions of zero net tissue stress. Heatmap indicates magnitude of cell-level isotropic stress, Peff, with cells being under net tension (red) or compression (blue). A simulated Ras cluster was initialized in the center of the tissue (enclosed within black ring). Left: no additional contractility in cluster is shown. Right: 30% increase in cortical contractility, Γ, in cluster is shown.(F) Simulated tissues from (E), with heatmap showing the orientation of the principal axis of cell shape relative to the cluster (as shown in G).(G) From confocal images, the shapes of host cells neighboring the clusters (dark purple: 1–3 cells from cluster; light purple: 4–6 cells; pink: 7+ cells) were traced and cell shape orientation (long-axis) relative to the cluster was measured (two examples in white are shown).(H) Rose histograms showing the orientation of wild-type cells’ long axes 1–3 cells from GFP-control (red), GFP-kRasV12 (green), and GFP-cMYC (yellow) clusters, relative to the cluster, with the total number of cells analyzed across all embryos in each data group in 10° bins. Kruskal-Wallis test: GFP versus GFP-kRasV12 p < 0.01 and GFP versus GFP-cMYC p > 0.9999; n = 431 cells from 7 GFP embryos, 224 cells from 5 GFP-kRasV12 embryos, and 348 cells from 7 GFP-cMYC embryos.(I) Cumulative distributions of cell shape orientation relative to cluster (as shown in G), from experiments (magenta) and simulations (green). Ras clusters were simulated with varying degrees of increased cortical contractility, Γ.(J) Wasserstein distance between experiments and simulations for cumulative distributions in (I) and Figure S2E. Discrete intervals on the x axis relate to shades of green in (I). For every contractility interval, the y axis shows the sum of the Wasserstein distances over the three distance categories (1–3, 4–6, and 7+ cells). The best fit is found at a 9% increase in contractility, where summed Wasserstein distance is minimized.See also Figure S2.
	Figure S2: Analysis of mechanical strain and cell shape in and around kRasV12 clusters. Related to Figure 2. (A) Recoil measurements for wild-type or GFP-kRasV12 cells adjacent to the cluster boundary (solid lines) compared to recoil within cluster and wild-type cells away from the boundary (dashed lines: data sets shown in Figure 2C); n=10 cells for each sample, error bars are SEM. (B) Initial recoil velocity calculated from recoil measurements in (A) with data from Figure 2D shown as comparison (dashed); One-way ANOVA: **p<0.01, no other difference was significant, n=10 cells for each sample, error bars are SEM. (C-F) Rose histograms show the orientation of wild-type cells long-axes 4-6 cells (C and D) and 7 or more (E and F) cells from GFP-control (C and E) or GFP-kRasV12 (D and F) cell clusters, relative to the cluster, with the total number of cell divisions that were analysed across all embryos each data group in 10° bins. Kruskal-Wallis test: 4-6 cells: p=0.1572, n=433 cells from 5 GFP-control embryos and 240 cells from 5 GFP-kRasV12 embryos. 7+ cells: p>0.9999, n=690 cells from 5 GFP-control embryos and 344 cells from 4 GFP-kRasV12 embryos. (G-H) Violin plots of cell area (G) and cell circularity (H) for cells within and surrounding GFP-kRasV12 and GFP clusters. No statistically significant differences were observed (Kruskal-Wallis test, n = mean values for 5 and 7 embryos for kRasV12 and GFP, respectively). (I) Cumulative distributions of cell shape orientation relative to cluster, 7+ cells from the cluster edge, comparing experiments (magenta) and simulations (green). Ras clusters were simulated with varying degrees of increased cortical contractility, Γ.
	Figure 3. The wild-type epithelium responds to oncogene-expressing clusters with altered cell division(A and B) Dot plots showing the percentage of wild-type cells that divided per minute of time lapse at different distances from GFP, GFP-kRasV12, or GFP-cMYC clusters. (A) Kruskal-Wallis test: ∗p < 0.05 and ∗∗∗p < 0.001; n = 8 GFP-control, 10 GFP-kRasV12, and 9 GFP-cMYC embryos. Error bars are SEM. (B) Paired t tests were performed; n = 8 GFP, 10 GFP-kRasV12, and 9 GFP-cMYC embryos.(C–E) Snapshots from confocal microscopy time lapses of representative embryos showing the orientation of cell divisions that occurred in wild-type cells: colored lines were drawn, connecting the dividing anaphase nuclei, and are shown cumulatively for the entire time lapse in one snapshot. White lines label divisions 1–3 cells from the cluster, and yellow lines mark divisions 4–6 cells away. Scale bars represent 100 μm.(F–H) Rose histograms showing cell division orientation up to 6 cells away from (F) GFP control, (G) GFP-kRasV12, and (H) GFP-cMYC clusters, with the total number of cell divisions analyzed across all embryos in each data group in 10° bins. Kruskal-Wallis test: GFP versus GFP-kRasV12 p < 0.05 and GFP versus GFP-cMYC p > 0.9999; n = 88 divisions from 8 GFP embryos, 193 divisions from 11 GFP-kRasV12 embryos, and 231 divisions from 9 GFP-cMYC embryos.See also Figure S3.
	Figure S3: Further Characterisation of Wild-type Cell Behaviour in Xenopus laevis Embryos with Oncogene-Expressing Cell Clusters. Related to Figure 3. (A) Stills from a confocal microcopy time-lapse show the quantification of cell division orientation within the epithelial plane, relative to a GFP-expressing cluster. An angle of 90° indicates a division perpendicular to the border of the cluster, whereas an angle of 0° indicates a division parallel to it. (B) Bar chart shows the average percentage of cell divisions in 30° bins that occurred in wild-type cells up to 3 cells from GFP, GFP-kRasV12 or GFP-cMYC clusters. Kruskal-Wallis test *p<0.05; n=8 GFP, 9 GFP-kRasV12 and 9 GFP-cMYC embryos. Error bars show SEM. (C-D) Rose histograms show cell division orientation, relative to the cluster edge, of wild-type cells 7+ cells from (C) control-GFP or (D) GFP-kRasV12 clusters, in 10° bins. Kruskal-Wallis test: p>0.9999: shows no significant difference between distributions; Chi- squared tests show no significant difference from uniform distribution for (C) or (D); n=120 divisions from 8 GFP-control embryos and 212 divisions from 11 GFP-kRasV12 embryos. (E) Confocal microscopy image of a stage 10 Xenopus embryo injected with GFP-kRasV12 (green) mRNA in a single cell at the 32-cell stage; mCherry-H2B (red) mRNA was then injected into neighbouring cells at the 32-cell stage. Scale bar is 100 μm. (F) Images showing a representative ITLS, in a stage 38 embryo, that had a GFP-kRasV12 cluster and wild-type cells labelled with cherry-H2B at stage 10. Wild-type cells (red) can be seen contributing to the ITLS. Scale bar represents 500 μm. (G) Categorisation of ITLS from GFP-kRasV12 embryos according to quantity of wild-type cells present in ITLS (ITLS in F, categorised as “high”). Error bars show SEM, n=6 independent experiments, 39 embryos.
	Figure S4: Further Characterisation of the Depletion of Myosin ll in Oncogene- Expressing Cell Clusters. Related to Figure 4. (A) Quantification of fluorescence intensity for phospho-myosin II staining in stage 10 embryos with a GFP-kRasV12 cluster. Fluorescence intensity in kRasV12 cells is shown as a fold-change compared to wild-type cells in the same embryo (*p<0.01, Mann Whitney, n=6 embryos. (B) Confocal slice of C-cadherin staining (magenta) in GFP-kRasV12 clusters (green) and surrounding wild-type tissue. Scale bar represents 20μm. (C) Quantification of mean animal cap thickness at GFP and GFP-RhoAQ63L clusters in stage 10 embryos (p<0.05, Unpaired t- test, n = 24 and 30 embryos respectively). (D) Quantification of mean animal cap thickness at GFP/Ctrl MO, GFP-kRasV12/Ctrl MO and GFP-kRasV12/MHC MO clusters in stage 10 embryos (***p<0.001, Kruskal-Wallis, n = 24, 32 and 19 embryos respectively). (E) Dot plot shows the average percentage of cells per minute that divided in clusters that were co-injected with GFP, GFP-kRasV12 or GFP-cMYC mRNA and either control morpholino (Ctrl MO) or myosin heavy chain llB morpholino (MHC MO). GFP: Kruskal-Wallis test: n=4 GFP/Ctrl MO embryos, 5 GFP/MHC MO, 5 kRasV12/Ctrl MO and 7 kRasV12/MHC MO, 3 GFP-cMYC/Ctrl MO and 4 GFP- cMYC/Ctrl MO embryos. Error bars are SEM. (F) Bar chart shows the average number of minutes between nuclear envelope breakdown and the separation of daughter nuclei in anaphase. Kruskal-Wallis test: ****p<0.0001, ***p=0.0007 n=12 GFP/Ctrl MO cells, 7 GFP/MHC MO, 12 kRasV12/Ctrl MO, 9 kRasV12/MHC MO, 12 GFP-cMYC/Ctrl MO and 4 GFP- cMYC/Ctrl MO. Error bars are SEM. (G-H) Rose histograms show the orientation of wild-type cell long-axes up to 3 cells or from myosin ll deficient (F) GFP clusters or (G) GFP-cMYC clusters, relative to the cluster, in 10° bins. Kruskal-Wallis test performed against GFP/Ctrl MO shown in Figure 4G: GFP/Ctrl MO vs GFP/MHC MO p>0.9999, GFP/Ctrl MO vs GFP- cMYC/MHC MO p=0.0803, n=325 cells from 6 GFP/Ctrl MO embryos, 107 cells from 7 GFP/MHC MO embryos and 128 cells from 8 GFP-cMYC/MHC MO embryos. (I-J) Rose histograms show cell division orientation of wild-type cells up to 6 cells from myosin ll deficient (H) GFP clusters or (I) GFP-cMYC clusters, relative to the cluster in 10° bins. Kruskal-Wallis test performed against GFP/Ctrl MO shown in Figure 4H: GFP/Ctrl MO vs GFP/MHC MO p>0.9999, GFP/Ctrl MO vs GFP-cMYC/MHC MO p>0.9999, n=58 divisions from 6 GFP/Ctrl MO embryos, n=99 divisions from 7 GFP/MHC MO embryos and 80 divisions from 8 GFP- cMYC MHC MO embryos.
	Figure 4. Actomyosin contraction in cluster is required to generate strain and alter cell division in wild-type tissue(A and B) Confocal images of fixed, stage 10 embryos with a GFP-kRasV12 cluster, stained for (A) phosphorylated myosin II (magenta), single-headed arrows highlight tricellular junctions with increased phospho-myosin II in GFP-kRasV12 cells compared to wild-type tissue (double-headed arrows), and (B) F-actin (phalloidin; magenta), single-headed arrows highlight increased F-actin at the cell cortex in the GFP-kRasV12 cluster compared to wild-type tissue (double-headed arrows).(C) Rose histograms showing the orientation of wild-type cells’ long axes up to 6 cells from GFP-control (red) or GFP-RhoAQ63L (orange) cell clusters, relative to the cluster, in 10° bins. Kolmogorov-Smirnov test: p < 0.05; n = 298 cells from 6 GFP-control embryos and 299 cells from 6 GFP-RhoAQ63L embryos.(D) Rose histograms showing cell division orientation relative to GFP-control (red) or GFP-RhoAQ63L (orange) clusters, with the total number of cells in 10° bins. Kolmogorov-Smirnov test: p < 0.05; n = 98 divisions from 10 GFP-control embryos and 174 divisions from 9 GFP-RhoAQ63L embryos.(E) Dot plot showing percentage of wild-type cells that divided per minute of time lapse at different distances from GFP-control or GFP-RhoAQ63L clusters. One-way ANOVA: ∗p < 0.05; n = 7 GFP-control and 9 GFP-RhoAQ63L embryos. Error bars are SEM.(F) Confocal microscopy image shows a myosin-II-deficient GFP-kRasV12 cell cluster. Arrows highlight “butterfly nuclei.”(G) Rose histograms showing the orientation of wild-type cell long axes up to 3 cells from GFP/Ctrl MO (red) or myosin-II-deficient (MHC MO) GFP-kRasV12 (light green) cell clusters, in 10° bins. Kruskal-Wallis test: p > 0.9999; n = 325 cells from 6 GFP/Ctrl MO embryos and 368 cells from 7 GFP-kRasV12/MHC MO embryos.(H) Rose histograms show cell division orientation up to 6 cells from (D) GFP/Ctrl MO (red) or GFP-kRasV12/MHC MO (light green) cell clusters, in 10° bins. Kruskal-Wallis Test: p = 0.9327; n = 58 divisions from 6 GFP/Ctrl MO embryos and 132 divisions from 9 GFP-kRasV12/MHC MO embryos.(I) Dot plot shows percentage of wild-type cells that divided per minute of time lapse, up to 3 cells from GFP, GFP-kRasV12, or GFP-cMYC control morpholino clusters or myosin-II-deficient GFP, GFP-kRasV12, or GFP-cMYC clusters. Kruskal-Wallis test: ∗p < 0.05; n = 5 GFP/Ctrl MO embryos, 11 GFP/MHC MO, 6 GFP-kRasV12/Ctrl MO, 13 GFP-kRasV12/MHC MO, 3 GFP-cMYC/Ctrl MO, and 9 GFP-cMYC/MHC MO embryos.(J) Images of representative embryos at stage 38 selected for presence of GFP-kRasV12 clusters at stage 10 and co-injected at 32-cell stage with Ctrl MO or MHC MO. Arrow indicates formation of ITLS in GFP-kRasV12/Ctrl MO embryo, but not GFP-kRasV12/MHC MO.(K) Quantification of ITLS formation at stage 38 in kRasV12/Ctrl MO and GFP-kRasV12/MHC MO embryos (p < 0.01; Mann Whitney test; n = 7 independent experiments; a total of 163 GFP-kRasV12/Ctrl MO and 124 GFP-kRasV12/MHC MO embryos were assessed). Error bars are SEM.Scale bars represent 100 μm in (A), (B) (main image), and (F); 50 μm in (B) (zoom-ins); and 500 μm in (J). See also Figure S4.

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