Key resources table
| REAGENT or RESOURCE | SOURCE | IDENTIFIER |
|---|---|---|
| Antibodies | ||
| Rabbit p53 | Cell Signaling | Cat#: 32532; RRID: AB_2757821 |
| Rabbit KMT2D | Sigma-Aldrich | Cat#: HPA035977; RRID: AB_10670673 |
| Ki-67 Monoclonal Antibody | Thermo Fisher Scientific | Cat#: 14–5698-82; RRID: AB_10854564 |
| Purified anti-Keratin 5 Antibody | BioLegend | Cat#: 905504; RRID: AB_2616956 |
| Anti-p40 DeltaNp63 Antibody | Abcam | Cat#: ab203826 |
| p44/42 MAPK (Erk1/2) Antibody | Cell Signaling | Cat#: 9102; RRID: AB_330744 |
| Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) Antibody | Cell Signaling | Cat#: 9101; RRID: AB_331646 |
| Phospho-HER2/ErbB2 (Tyr1221/1222) Antibody | Cell Signaling | Cat#: 2243; RRID: AB_490899 |
| HER2/ErbB2 (29D8) Rabbit mAb | Cell Signaling | Cat#: 2165; RRID: AB_10692490 |
| EGF Receptor Antibody | Cell signaling | Cat#: 2232; RRID: AB_331707 |
| Phospho-EGF Receptor (Tyr1068) (D7A5) XP® Rabbit mAb | Cell signaling | Cat#: 3777; RRID: AB_2096270 |
| Anti-Histone H3 (mono methyl K4) antibody | Abcam | Cat#: ab8895; RRID: AB_306847 |
| Anti-Histone H3 (acetyl K27) antibody | Abcam | Cat#: ab4729; RRID: AB_2118291 |
| Anti-Histone H3 (tri methyl K4) antibody | Abcam | Cat#: ab8580; RRID: AB_306649 |
| Anti-p75 NGF Receptor antibody | Abcam | Cat#: ab8875; RRID: AB_306828 |
| Monoclonal Anti-Acetylated Tubulin antibody | Sigma | Cat#: T7451; RRID: AB_609894 |
| CC10 Antibody (E-11) | Santa Cruz | Cat#: sc-365992; RRID: AB_10915481 |
| HSP90 (C45G5) | Cell signaling | Cat#: 4877; RRID: AB_2233307 |
| Mll4 polyclonal antibody | Diagenode | Cat#: C15310100 |
| Monoclonal Anti-β-Actin antibody | Sigma | Cat#: A5441; RRID: AB_476744 |
| Recombinant Anti-TTF1 antibody | Abcam | Cat#: ab133638; RRID: AB_2734144 |
| IRDye 800CW Donkey anti-Rabbit IgG Secondary Antibody | LICOR | Cat#: 926–32213; RRID: AB_621848 |
| IRDye 680RD Donkey anti-Mouse IgG Secondary Antibody | LICOR | Cat#: 926–68072; RRID: AB_10953628 |
| Goat anti-Mouse Secondary Antibody, Alexa Fluor 488 | Thermo Fischer Scientific |
Cat#: A-11001; RRID: AB_2534069 |
| Goat anti-Rabbit Secondary Antibody, Alexa Fluor Plus 555 |
Thermo Fischer Scientific |
Cat#: A32732; RRID: AB_2633281 |
| Bacterial and virus strains | ||
| One Shot™ Stbl3™ Chemically Competent E. coli | Invitrogen | Cat#: C737303 |
| NEB® 5-alpha F’Iq Competent E. coli | NEB | Cat#: C2992H |
| Biological samples | ||
| Mouse sample | This manuscript | N/A |
| Patient-derived xenografts (PDX), PDX-1 (LX-515) and PDX-2 (LX-640) | Preclinical Therapeutics Program NYU Langone Health |
N/A |
| Patient-derived xenografts (PDX), PDX-3 and PDX-4 | Chinese Academy of Sciences | N/A |
| Chemicals, peptides, and recombinant proteins | ||
| Collagenase D | Roche | Cat#: 11088866001 |
| DNase I | Roche | Cat#: 10104159001 |
| Protease and phosphatase inhibitor cocktail | Thermo Fisher Scientific | Cat#: 78440 |
| RIPA Lysis and Extraction Buffer | Thermo Fisher Scientific | Cat#: 89900 |
| Blocking buffer | LICOR | Cat#: 927–50003 |
| DAPI | BioLegend | Cat#: 422801 |
| CCK-8 | Dojindo | Cat#: CK04 |
| Fluorescence Mounting Medium | DAKO | Cat#: S3023 |
| PowerUp™ SYBR™ Green Master Mix | Applied Biosystems | Cat#: 4367659 |
| Corning® Matrigel® Growth Factor Reduced (GFR) Basement Membrane Matrix |
Corning | Cat#: 354230 |
| Corning® Matrigel® Basement Membrane Matrix | Corning | Cat#: 354234 |
| PEG-it Virus Precipitation Solution | System Biosciences | Cat#: LV810A-1 |
| Advanced DMEM/F12 | Thermo Fisher Scientific | Cat#: 12634010 |
| DMEM/F-12 with 15 mM HEPES | StemCell Technologies | Cat#: 36254 |
| N2 Supplement (100x) | Life Technologies | Cat#: 17502048 |
| B27 Supplement 50x | Life Technologies | Cat#: A1895601 |
| N-Acetylcysteine | Thermo Fisher Scientific | Cat#: A15409.14 |
| h-EGF | Sigma Aldrich | Cat#: E9644 |
| Y-27632 | Selleck | Cat#: S1049 |
| BAMBANKER freeze medium | Fisher Scientific | Cat#: NC9582225 |
| Lipofectamine 3000 | Invitrogen | Cat#: L3000008 |
| Dynabeads™ Protein G for Immunoprecipitation | Thermo Fisher Scientific | Cat#: 10003D |
| Paraformaldehyde | Electron Microscopy Sciences | Cat#: 15714 |
| Afatinib | MCE | Cat#: HY-10261 |
| SHP099 | Wuxi AppTec | Customized synthesis |
| Critical commercial assays | ||
| Proteome Profiler Mouse Phospho-RTK Array Kit | R&D system | Cat#: ARY014 |
| Pierce™ BCA protein assay kit | Thermo Fisher Scientific | Cat#: 23225 |
| CUT&Tag-IT Assay Kit | Active Motif | Cat#: 53160 |
| Universal Mycoplasma Detection Kit |
ATCC | Cat#: 30–1012K |
| High-Capacity RNA-to-cDNA™ Kit | Thermo Fisher Scientific | Cat#: 4387406 |
| Deposited data | ||
| Data files for Omics data (RNA-seq, ChIP-seq, CUT&Tag and ATAC-seq) | This manuscript, GEO | GSE200505 |
| Public RNA-seq data of KrasG12D; Trp53−/− tumors | Deng et al,32 GEO | GSE137396 |
| Public RNA-seq data of normal mouse lung tissues | Mollaoglu et al,33 GEO | GSE118246 |
| Public RNA-seq data of human LUSC | TCGA | https://portal.gdc.cancer.gov |
| Experimental models: Cell lines | ||
| Trp53L/L organoids | This manuscript | N/A |
| Trp53−/− organoids | This manuscript | N/A |
| Trp53−/−; Kmt2d−/− organoids | This manuscript | N/A |
| Trp53−/−; Pten−/− organoids | This manuscript | N/A |
| Trp53−/−; Kmt2d−/− cells | This manuscript | N/A |
| Trp53−/−; Pten−/− cells | This manuscript | N/A |
| Trp53−/−; Pten−/−; Kmt2d−/− cells | This manuscript | N/A |
| Trp53−/−; Lkb1−/−; Pten−/− cells | This manuscript | N/A |
| HEK-293T | ATCC | Cat#: CRL-1573, RRID: CVCL_0063 |
| L-WRN | ATCC | Cat#: CRL-3276 |
| HARA | CCLE | RRID: CVCL_2914 |
| HCC-95 | CCLE | RRID: CVCL_5137 |
| EBC-1 | CCLE | RRID: CVCL_2891 |
| LK2 | CCLE | RRID: CVCL_1377 |
| Experimental models: Organisms/strains | ||
| Mouse: C57BL/6J | The Jackson Laboratory | JAX: 000664; RRID: IMSR_JAX:000664 |
| Mouse: B6(Cg)-Tyrc-2J/J (B6-Albino) | The Jackson Laboratory | JAX: 000058; RRID: IMSR_JAX:000058 |
| Mouse: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) | The Jackson Laboratory | JAX: 005557; RRID: IMSR_JAX:005557 |
| Mouse: Crl:NU-Foxn1nu (Nude) | Charles River | Cat#: 088 |
| Mouse: LSL-EGFR-T790M-L858R | Li et al.31 | N/A |
| Mouse: B6.129P2-Trp53tm1Brn/J (p53loxp) |
The Jackson Laboratory | JAX: 008462; RRID: IMSR_JAX:008462 |
| Oligonucleotides | ||
| See Table S2 | ||
| Recombinant DNA | ||
| psPAX2 | Addgene | Cat#: 12260 |
| pMD2.G | Addgene | Cat#: 12259 |
| lentiCRISPR v2-Blast | Addgene | Cat#: 83480 |
| lentiCRISPR v2-Blast-sgPten | This manuscript | N/A |
| lentiCRISPR v2-Blast-sgKmt2d-1 | This manuscript | N/A |
| lentiCRISPR v2-Blast-sgKmt2d-2 | This manuscript | N/A |
| pSpCas9(BB)-2A-GFP | Addgene | Cat#: 48138 |
| pX458-sgSHP2 | Fedele et al.42 | N/A |
| lentiCas9-Blast | Addgene | Cat#: 52962 |
| pLV-sgControl | This manuscript | N/A |
| pLV-sgKMT2D-1 | This manuscript | N/A |
| pLV-sgKMT2D-2 | This manuscript | N/A |
| Software and algorithms | ||
| GraphPad Prism V9 | GraphPad Software Inc. | http://www.graphpad.com |
| R 4.0.4 | R | https://www.r-project.org/ |
| R Studio | RStudio | https://www.rstudio.com/ |
| Fiji v2.0.0 | ImageJ | https://imagej.net/software/fiji/ |
| Snapgene | Snapgene | https://www.snapgene.com/ |
| GEPIA2 | Tang et al.24 | http://gepia2.cancer-pku.cn |
| DESeq2 | Love et al.69 | https://bioconductor.org/packages/release/bioc/html/DESeq2.html |
| Gene Set Enrichment Analysis (GSEA) | Broad Institute.70 | http://software.broadinstitute.org/gsea/index.jsp |
| Cbioportal | Cbioportal.71, 72 | https://www.cbioportal.org/ |
| Bowtie2 | Langmead et al.73 | https://bowtie-bio.sourceforge.net/bowtie2/index.shtml |