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1 Supplementry Informtion Titles Journl: Nture Medicine Article Title: Corresponding Author: Modelling colorectl cncer using CRISPR-Cs9-medited engineering of humn intestinl orgnoids Toshiro Sto Supplementry Item & Numer Supplementry Figure 1 Supplementry Figure 2 Supplementry Figure 3 Supplementry Figure 4 Supplementry Figure 5 Supplementry Figure 6 Supplementry Figure 7 Supplementry Figure 8 Supplementry Figure 9 Supplementry Tle 1 Supplementry Tle 2 Supplementry Tle 3 Supplementry Tle 4 Title or Cption Estlishment of CRISPR-Cs9-engineered orgnoids. CRISPR-Cs9-medited introduction of muttions in driver pthwys. Het mps of differentilly expressed genes in engineered orgnoids. Estlishment of lentivirlly engineered orgnoids. Tumour grfts of lentivirlly engineered orgnoids Tumour grfts of CRISPR-Cs9-engineered orgnoids nd CRC orgnoids. Glol gene expression of denom, engineered nd CRC orgnoids. Sequence nlysis of engineered orgnoids. Estlishment of engineered denom orgnoids. Summry of clinicl informtion Gene trgeting efficiency of CRISPR-Cs9 in humn colonic orgnoids. Sequence nlysis of predicted off-trget loci of CRISPR/Cs- 9 edited orgnoids. Oligonucleotides used in this study. AIP Checklist 1

2 Supplementry Figure 1 Orgnoids CRISPR Selection SURVEYOR ssy Trypsiniztion Sequencing Cloning Norml orgnoids Adenom orgnoids CRC orgnoids Norml1 Norml2 Norml3 Ade1 Ade2 Ade3 Ade4 Ade5 CRC1 CRC2 CRC3 CRC4 CRC5 CRC6 CRC7 CRC8 CRC9 CRISPR-Cs9 engineering Lentivirusengineering Lentivirusengineering CRISPRengineering c Norml1 (WR ENA) A (ENA) AST AKST AKSTP (E+TGF+Nut) (None) (MEKi) A: 3 p (SD) del (5/8), 11p del (3/8) S: 3 p (V370) del, lrge ins T: 2 p del (4/8), 2 p del (4/8) K: V12G (direct), P: E545K (5/8) (S.Fig.8) Norml2 (WR ENA) A (ENA) AS AST AKST AKSTP (E+TGF) (E+Nut) (None) (MEKi) A: 1 p del(8/8) S: 2 p ins (4/8), 51 p ins (4/8) T: 1 p del (8/8) K: V12G (direct), P: E545K (3/8) (S.Fig.8c) Supplementry Figure 1: Estlishment of CRISPR-Cs9-Engineered Orgnoids. () Summry of strtegy for CRISPR-Cs9-sed orgnoid engineering. () Summry of clinicl informtion for orgnoids used in this study. R: Rectum, FAP: fmilil denomtous polyposis. (c) Genertion of second nd third line of CRISPR-Cs9-engineered orgnoids. Sequences of del (deletions) nd ins (insertions) re shown in Supplementry Fig. 8,c.

3 Supplementry Figure 2 g h (p) A WT A- A WT A- -ctenin (k) perk WT perk 200 -ctin 2 KI ERK 100 c d (p) 300 S WT S- S WT S- i 200 -ctin 100 * pakt AKT * e f (p) T WT T- T WT T ctin 100 Supplementry Figure 2: CRISPR-Cs9-medited introduction of muttions in driver pthwys. (, c, e) SURVEYOR ssy to detect CRISPR-Cs9-medited clevge t the APC-trgeted (A-), -trgeted (S-) nd -trgeted (T-) orgnoids. WT: Wild type. (, d, f) Western lot nlysis of engineered orgnoids. Expression of -ctenin ( consequence of Wnt ctivtion), nd re indicted. -ctin, loding control. (g) Southern lot nlysis of DNA isolted from control nd KRAS G12V orgnoid clones. Proes for the Southern lot nlyses re indicted in (Fig. 1g). (h) Western lot for phospho-erk nd totl ERK in KRAS WT or KRAS G12V orgnoids. (i) Western lot nlysis of phospho-akt nd totl AKT in KRAS G12V nd KRAS G12V PIK3CA E545K orgnoids. *, non-specific nds.

4 Supplementry Figure 3 Adenom Engineered CRC CA1 REG4 GCG LYZ CHGA PLA2G2A TFF1 TFF2 SPINK4 MUC2 ETV4 TRPM2 EREG KRT Supplementry Figure 3. Het mps of differentilly expressed genes in engineered orgnoids. Gene expression dt of denom orgnoids is dded on the het mps shown in Fig. 2g.

5 Supplementry Figure 4 WR ENA ENA Hygro G418 Puro Zeo Norml Orgnoid 2 B BK BKS BKST BKSTP Lentivirus CTNNB1S33Y KRASG12V PGK-Hygro r KD PGK-Neo r KD PGK-Puro r PIK3CA E545K PGK-Zeo r c d Cont Cont B S33Y Cont K G12V -ctenin perk1/2 S KD -ctin Erk1/2 -ctin e Control KD f Cont P E454K pakt g -ctin Nutlin-3 ENA NA TGF Nutlin3 MEKi Akt BKSTP Supplementry Figure 4: Estlishment of Lentivirlly Engineered Orgnoids. () Selection strtegy for lentivirus-sed engineered orgnoids. Arevitions for overexpressed or knockdown genes were s follows: B, constitutive ctive form of -ctenin; K, KRAS G12V ; S, knockdown (KD) of ; T, KD of ; P, PIK3CAE545K. (-f). Vlidtion of lentivirus-sed engineered orgnoids. () Western lot nlysis illustrtes upregultion of the ctive form of -ctenin in B orgnoids (BS33Y). Cont: wild-type control orgnoids. (c) Downstrem ERK ctivtion in control wild-type KRAS or KRASG12V-trnsduced (K G12V ) orgnoids under EGF removed culture conditions. Western lot nlyses of the phosphorylted form of ERK1/2 (perk) nd totl ERK protein. (d) Knockdown of protein. Nutlin-3 tretment induced protein in wild-type orgnoids. The effect of Nutlin-3 ws olished in knockdown ( KD ) orgnoids. (e) Knockdown of protein in -shrna trnsduced orgnoids (S KD ). (f) Downstrem PI3 kinse ctivtion in control wild-type PIK3CA or PIK3CA E545K -trnsduced orgnoids under EGF removed culture conditions. Western lot nlyses of the phosphorylted form of Akt (pakt) nd totl Akt protein. (g) Response to niche modulted culture conditions (See Figure 2B for the revitions) in BKSTP-orgnoids.

6 Supplementry Figure 5 1M 2M 25 B 20 1M 2M BK BKS BKST GFP re (mm 2 ) BKSTP 0 B BK BS BT BKS BKST BKSTP c HE PAS Ki67 KRT20 Supplementry Figure 5: Tumour Grfts of Lentivirlly Engineered Orgnoids () Photogrphs of representtive tumours derived from indicted orgnoids in kidney sucpsules of NOG mice. Xenotrnsplnted tumours re lelled y EGFP. Tumours were isolted 1 month (1M) or 2 months (2M) fter trnsplnttion. Scle r = 5 mm. () The verge surfce re of xenogrfts derived from orgnoids indictes the tumour size t 1 or 2 months fter trnsplnttion (n=4). Error rs indicte s.e.m. (c) Histochemicl nlysis of BKSTP-orgnoids isolted 1 month fter the trnsplnttion. Indicted stining ws shown. KRT: cytokertin 20.

7 Supplementry Figure 6 HE Ki67 PAS CK20 AKST 1M CRC 1M HE -ctenin CK20 Supplementry Figure 6: Tumour Grfts of CRISPR-Cs9-Engineered Orgnoids nd CRC Orgnoids. Representtive histochemicl nlysis of kidney sucpsule xenogrfts derived from AKST-orgnoids () or CRCorgnoids () isolted 1 month fter trnsplnttion. Indicted stining ws shown. KRT20: cytokertin 20. Scle r = 500 m

8 Supplementry Figure 7 Adenom/Engineered Ade CIN TSP 2000 CRC PC Ade 0 Ade CIN TS Ade CIN TSK PC1 Supplementry Figure 7: Glol gene expression of denom, engineered nd CRC orgnoids. PCA nlysis including gene expression of Ade CIN TSK- nd Ade CIN TSP- orgnoids (grey). Engineered orgnoids from norml epithelium (lue), Adenom orgnoids (red) nd CRC orgnoids (rown) were indicted. Arrows indicte engineering from prentl denom orgnoids.

9 Supplementry Figure 8 APC APC 7 p (SD) del (8/8) 3 p (V371) del (3/6) 2 p del (3/6) 1 p ins (4/8) 18 p del (4/8) 3 p (SD) del (5/8) 11 p del (3/8) 3 p (V370) del (8/8) p ins (8/8) 2 p del (4/8) 2 p del (4/8) c APC 1 p del (8/8) 2 p ins (4/8) 51 p ins (4/8) 1 p del (8/8) d N369K/V370 del (8/8) 1 p del (3/6) 2 p del (3/6) e 3 p del NV369N (4/8) 1 p del (4/8) 1 p del (8/8) Supplementry Figure 8. Sequence nlysis of engineered orgnoids. (-c) Sequences of AKSTP orgnoids shown in Fig. 2 nd Supplementry Fig.1c. (d, e) Sequences of Ade ST orgnoids (d) or Ade CIN TSK orgnoids (e) shown in Fig. 4. SD: splicing donor sites, del: deletion, ins: insertion (underlined). Trget regions were mplified y PCR nd sucloned to E. Coli. Indicted numer of suclones were sequenced. Note tht V370 is in conserved loop/helix region of MH2 domin nd criticl for TGF-/BMP signlling (Shi, Y., Ht, A., Lo, R.S., Mssgue, J. & Pvletich, N.P. A structurl sis for muttionl inctivtion of the tumour suppressor Smd4. Nture 388, (1997))

10 Supplementry Figure 9 Adenom1 (ENA) Lentivirus Ade 1 T (Puro) Ade 1 TS (Neo) Ade 1 TSK (Hygro) Adenom 2 (ENA) CRISPR Ade 2 TSK (EGFRi+TGF+Nut) Adenom1 Ade 1 TSK Ade 2 TSK c Are of metstses log (mm 2 ) ATKSP Adenom Ade T Ade S Ade ST Ade CIN TS Ade CIN TSP Ade CIN TSK CRC Adenom1 Ade 1 TSK Ade 2 TSK Supplementry Figure 9. Estlishment of engineered denom orgnoids. () Selection strtegy of second nd third line of engineered denom orgnoids. () Photogrphs of representtive tumours derived from indicted orgnoids in kidney sucpsules of NOG mice. Xenotrnsplnted tumours re lelled y EGFP. Tumours were isolted 1 month (1M) fter trnsplnttion. Scle r = 5 mm. (c) Dt of metstsized lesions from Adenom1, Ade1TSK nd Ade2TSK orgnoids is dded on the sctter plot shown in Fig. 4e. Plots represent EGFP + re of metstsized lesions in liver. n=4 mice per genotype.

11 Supplementry Tle 1 Ptient Tumor Ptient Clinicl Tumor Ptient Prior Orgnoid ID ID Loction Disese Stge Histology Sex tretment #1 CRC1 R CRC Stge IV Moderte F None #1 CRC2 R CRC Stge IV Moderte F None #1 CRC3 Liver CRC Stge IV Moderte F None #2 CRC4 Liver CRC Stge IV Moderte M None #3 CRC5 R CRC Stge IV Moderte F None #4 CRC6 Distl CRC Stge IIIA Well M None #5 CRC7 Proximl CRC Stge IIA Moderte F None #6 CRC8 Proximl CRC Stge II Moderte M None #7 CRC9 Distl CRC Stge I Well M None #8 Adenom1 (Ade1) Colon NS FAP F None #9 Adenom2 (Ade2) Colon NS FAP F None #10 Adenom3 (Ade3) Colon NS FAP M None #11 Adenom4 (Ade4) Colon NS FAP M None #11 Adenom5 (Ade5) Colon NS FAP M None #12 Norml1 Proximl CRC Stge 0 F None #13 Norml2 Distl CRC Stge 0 M None #10 Norml3 Colon NS FAP M None Supplementry Tle 1. Summry of Clinicl Informtion. NS: not specified. F: femle, M: Mle.

12 Supplementry Tle 2 Recipient Cells CRISPR/Cs9 No. of electroported cells Ave. no. of recovered orgnoids (n=3) Ave. no. of selected orgnoids Correctly trgeted clones Norml PiggyBc-GFP-Puro/APC (+Puro) N.A. Norml PiggyBc-GFP-Puro/APC (-Wnt) 3/3 Norml APC (-Wnt) 3/3 Norml APC/ 1x10 5 N.A. 2 (-Wnt/+BMP4) 2/2 A PiggyBc-GFP-Puro/ (+Puro) N.A. A PiggyBc-GFP-Puro/ (+Nutlin) 2/2 A KRAS (Knock-in) 1x10 5 N.A. 3 (+EGFRi) 3/3 AKST PIK3CA (Knock-in) 1x10 5 N.A. 3(+EGFRi/MEKi) 2/3 Supplementry Tle 2. Gene Trgeting efficiency of CRISPR-Cs9 in humn colonic orgnoids. Summry of the genome engineering efficiency. Indicted numer of dissocited cells from Norml, A-orgnoids or AKSTorgnoids were electroported with indicted sgrna. The experiments were performed in triplicte nd verge numer (Ave. No.) of recovered orgnoids ± s.e.m is shown. After electroportion, round 1-5 % of electroported cells were recovered. In some experiments, Piggy-Bc GFP-Puro vectors were co-electroported to determine the efficiency of gene introduction. The ntiiotics - or niche fctor- selected orgnoids were verified y Snger sequencing nlysis.

13 Supplementry Tle 4 mirna trget sequence mirna #1 mirna #2 mirna #1 mirna #2 TCCACTACAACTACATGTGTA AGTCTGTGACTTGCACGTACT GGTGTGCAGTTGGAATGTAAA GGTGGAGAGAGTGAAACATTT CRISPR trget sequence APC CRISPR CRISPR #1 CRISPR #2 CRISPR KRAS CRISPR PIK3CA CRISPR GGCAACTTCTGGTAATGGTC AGG GCTGAAGATGGCCGTTTTGG TGG GTCAACTCTCCAATGTCCAC AGG GAATGAGGCCTTGGAACTCA AGG GCATTTTTCTTAAGCGTCGA TGG TCTCTCTGAAATCACTGAGC AGG Donor ssoligo PIK3CA Donor ssoligo (nti-sense) AGCACTTACCTGTGACTCCATAGAAAATCTTTCTCtTGCTtgGTGATTTC Primers for SURVEYOR Assy APC SURVEYOR-F APC SURVEYOR-R #1 SURVEYOR-F #1 SURVEYOR-R #2 SURVEYOR-F #2 SURVEYOR-R SURVEYOR-F SURVEYOR-R CGACCGCCAATCGTACTGGAGG GACAGCACATTGGTACTGAATGC TATAAAAGCAAATTAACCCATGT TTACAAAAAATACTGAAAAGCAC GAGAGACATTTAAGGTTCC ACAATTAAGATGGAGTGCT CAGCTGTATAGGTACTTGAAGTGCAGTTT CAATGAGATGGGGTCAGCTGCCTTTG Supplementry Tle 4: Oligonucleotides used in this study.

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