SUPPLEMENTARY INFORMATION

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1 doi: /nature22977 Supplementary Data 1 Fig. 4d + CM (no MDK) + CM (MDK) h 12h 24h h 12h 24h P- P- Fig. 4e CM GoF CM LoF-M5 CM GoF MDK Vehicle Rapamycin Torin VEGFR3 P- β-actin VEGFR3 P- β-actin

2 RESEARCH SUPPLEMENTARY INFORMATION Supplementary Table S1 Line Stage BRAF PTEN N-ras c-kit CDK4 MET V600E WT WT WT WT WM35 RGP V600E Mutant WT WT WT WM902B MET V600E WT WT WT WT WM115 VGP V600D Hem Del WT WT WT 451LU Xenograft MET V600E WT WT WT WT UACC-62 MET V600E Mutant WT WT WT SK-Mel-28 MET V600E MU WT WT R24C SK-Mel-103 MET WT WT Q61R WT WT SK-Mel-147 MET WT WT Q61R WT WT Table S1. Human melanoma cell lines used in this study. Genetic information are as described in Soengas et al. Nature 2001 and 2

3 RESEARCH Supplementary Table 2 Gene symbols 451LU vs SK-Mel-103 vs SK-Mel-28 vs MDK PRRT PROCR RPL RPL AGRN CD SDC TMSB IGF2BP IGF2BP CTSZ RNPEP CALU ILF HNRNPK RPS15A TUBB4A DBN SRP CAPNS ITGB RBM PLAUR RHOB ALCAM FLG CBR RPL RPS3A LGALS RPS TUBB RPLP RPS RUVBL HSD17B PSMD RPLP TUBA1C TAOK MARCKSL IGF1R DAAM FXYD Table S2. Pro-metastatic factors identified by proteomic analyses of the secretome of the indicated cell lines. Shown are differential ratios of protein expression (Log2 scale) estimated with respect to basal levels in the nonlymphangiogenic cell line. Additional filters were applied to remove factors present in the non-metastatic WM35, which does not activate distal lymphangiogenesis. 3

4 RESEARCH SUPPLEMENTARY INFORMATION Supplementary Table 3 MDK/NEG UP & shm1/shc DOWN & shm5/shc DOWN MDK/NEG DOWN & shm1/shc UP & shm5/shc UP MDK/NEG shm1/shc shm5/shc MTOR_UP.N4.V1_UP <0.001 <0.001 <0.001 HINATA_NFKB_IMMU_INF <0.001 <0.001 <0.001 LTE2_UP.V1_DN < STK33_UP < <0.001 EGFR_UP.V1_UP <0.001 <0.001 <0.001 CAMP_UP.V1_UP < <0.001 BMI1_DN_MEL18_DN.V1_UP <0.001 < E2F1_UP.V1_DN < <0.001 HOXA9_DN.V1_UP <0.001 ALK_DN.V1_UP MEL18_DN.V1_UP RB_P107_DN.V1_DN <0.001 ESC_J1_UP_EARLY.V1_DN KRAS.300_UP.V1_DN RPS14_DN.V1_UP SIRNA_EIF4GI_UP DCA_UP.V1_UP P53_DN.V2_UP IL15_UP.V1_DN VEGF_A_UP.V1_UP <0.001 <0.001 CAHOY_ASTROGLIAL HINATA_NFKB_MATRIX RB_P107_DN.V1_UP <0.001 <0.001 <0.001 PRC2_EDD_UP.V1_UP <0.001 <0.001 <0.001 CSR_LATE_UP.V1_UP <0.001 <0.001 <0.001 HOXA9_DN.V1_DN < E2F3_UP.V1_UP <0.001 <0.001 <0.001 E2F1_UP.V1_UP <0.001 <0.001 <0.001 MEK_UP.V1_UP < <0.001 LTE2_UP.V1_UP < <0.001 RPS14_DN.V1_DN <0.001 <0.001 <0.001 EGFR_UP.V1_DN <0.001 <0.001 <0.001 KRAS.DF.V1_UP <0.001 <0.001 <0.001 GCNP_SHH_UP_EARLY.V1_UP <0.001 <0.001 <0.001 TBK1.DF_UP < RB_DN.V1_UP < <0.001 ERB2_UP.V1_UP < GCNP_SHH_UP_LATE.V1_UP <0.001 <0.001 <0.001 PRC2_EZH2_UP.V1_UP < <0.001 VEGF_A_UP.V1_DN <0.001 <0.001 <0.001 ESC_V6.5_UP_LATE.V1_UP < RAF_UP.V1_UP PDGF_UP.V1_UP < P53_DN.V1_UP IL21_UP.V1_DN CRX_NRL_DN.V1_UP KRAS.AMP.LUNG_UP.V1_UP PRC2_SUZ12_UP.V1_UP <0.001 PRC1_BMI_UP.V1_UP ALK_DN.V1_DN ATF2_UP.V1_UP SRC_UP.V1_DN PRC2_EZH2_UP.V1_DN SIRNA_EIF4GI_DN ATM_DN.V1_DN TBK1.DN.48HRS_UP PDGF_ERK_DN.V1_DN <0.001 LEF1_UP.V1_UP NRL_DN.V1_UP Table S3. Signaling pathways identified by RNA seq to be controlled by MDK in lymphatic endothelial cells (LEC). Transcriptomic analyses were performed in MDK gain or loss of function studies (LoF and GoF) as indicated in Fig. 5a,b. Shown are Oncogenic Signatures found by gene set enrichment analyses (GSEA) to show a consistent (opposed) alterations in both settings. FDR for each gene set are shown. MDK/Neg, stands for comparative analyses of overexpressing MDK vs the parental (MDK negative control). shm1/shc and shm2/shc correspond to data from SK-Mel-147 expressing MDK sh1 or sh5, respectively, and analyzed with respect to the parental MDKexpressing cells transduced with shrna control. 4

5 RESEARCH Supplementary Table 4 Log2(FC) - MDK/NEG SK-Mel-147 shm1/shc SK-Mel-147 shm5/shc Gene Replicate 1 Replicate 2 Replicate 3 Replicate 1 Replicate 2 Replicate 3 Replicate 1 Replicate 2 Replicate 3 mtor Inflammation Cell Cycle PHGDH PHGDH SLC6A SLC6A9 CADM CADM3 HOXB HOXB9 CLDN CLDN1 ULBP ULBP1 CHAC CHAC1 SESN SESN2 STC STC2 CTH CTH DDIT DDIT4 ASNS ASNS SULT1E SULT1E1 LURAP1L LURAP1L SLC7A SLC7A11 PSAT PSAT1 TRIB TRIB3 SLC3A SLC3A2 CCL CCL20 GGT GGT5 ADM ADM2 PCK PCK2 ABI3BP ABI3BP MTHFD MTHFD2 VEGFA VEGFA IL IL6 RNF144B RNF144B SLC7A SLC7A5 NAV NAV3 MGC MGC16121 CXCL CXCL5 SLC4A SLC4A5 GPT GPT2 SLC1A SLC1A5 PMAIP PMAIP1 PSTPIP PSTPIP2 CYFIP CYFIP2 EFNB EFNB1 AOX AOX1 GLIPR GLIPR1 TLR TLR3 ICAM ICAM1 EIF4EBP EIF4EBP1 FGL FGL1 NUPR NUPR1 GARS GARS TMEM TMEM154 MRGPRX MRGPRX3 GPX GPX8 CBS CBS TLR TLR2 JDP JDP2 LST LST1 ANXA ANXA3 SLC16A SLC16A6 PLD PLD6 LPCAT LPCAT2 FAM107A FAM107A HNMT HNMT NSUN NSUN5 C6orf C6orf115 CRTAC CRTAC1 APLN APLN CENPQ CENPQ PRICKLE PRICKLE4 SETBP SETBP1 TUBD TUBD1 ALDH3A ALDH3A2 GJA GJA4 UCP UCP2 RDH RDH10 PDK PDK4 RADIL RADIL ATAD ATAD5 KHK KHK GAB GAB1 PARD6G PARD6G DCLK DCLK1 PPAP2A PPAP2A DTX DTX4 PSG PSG1 HCRTR HCRTR1 ABCA ABCA4 SCNN1B SCNN1B CLEC4M CLEC4M SESN SESN3 RCN RCN3 CA CA2 FAM111B FAM111B GUCY1A GUCY1A3 NTS NTS Table S4. MDK-induced changes in the LEC transcriptome. Data corresponds to gene lists and the corresponding expression changes shown in the heatmap of Fig. 5b. Genes with the indicated functions are labeled in red in the right table. 5

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