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P53 Promotes Peroxisomal Fatty Acid β-oxidation to Repress Purine metabolism and Mediate Tumor Suppression

ABSTRACT: Several studies suggested that p53 controls multiple metabolic pathways and their contribution to its tumor-suppressive functions. To investigate whether p53 might involve some unexplored metabolic pathways, Trp53fl/fl mice were crossed with Pvillin-Cre mice to generate Pvillin-Cre + Trp53fl/fl (VP) mice, and colorectal tumor model was induced by AOM/DSS. We analyzed the CRC tumor tissues from Trp53fl/fl and VP mice by RNA-seq.

ORGANISM(S): Mus musculus

PROVIDER: GSE189730 | GEO | 2023/03/02

REPOSITORIES: GEO

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Project description:Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition. To investigate the effect of single and combined mutations in colon and small intestine of mouse models, we have generated a large set of organoids across 16 different genotypes zooming in on microsatellite stable CRC (CMS2-4). This set of organoids includes villinCreER Apcfl/fl (A), villinCreER Apcfl/fl Trp53fl/fl (AP), villinCreER Apcfl/fl Trp53R172H/fl (AP2), villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl (AKP), villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl Smad4fl/+ (AKPS), villinCreER KrasG12D/+ (K), villinCreER KrasG12D/+ Trp53fl/fl (KP), villinCreER KrasG12D/+ Trp53fl/fl Rosa26N1ind/+ (KPN), villinCreER BrafV600E/+ Trp53fl/fl Rosa26N1ind/+ (BPN), villinCreER BrafV600E/+ Trp53fl/fl Rosa26N1ind/+ Alk5fl/fl (BPNA2), villinCreER Apcfl/fl KrasG12D/+ (AK), villinCreER Apcfl/fl KrasG12D/+ Trp53R172H/fl (AKP2), villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl Rosa26N1ind/+ (AKPN), villinCreER Apcfl/fl Trp53fl/fl Rosa26N1ind/+ (APN), villinCreER BrafV600E/+ Trp53fl/fl (BP), and villinCreER KrasG12D/+ Trp53fl/fl Rosa26N1ind/+ Alk5fl/fl (KPNA2).

Project description:We examined the transformation susceptibility of different cerebellar stem/progenitors by developing several new Group3 medulloblastoma murine models using orthotopic transplantation and in utero electroporation (EP)-based in vivo gene transfer with Cre/LoxP-mediated conditional Myc gene activation and loss of Trp53 function. We used microarrays to compared the transcriptome of these novel Group3 medulloblastoma mouse models to existing mouse models of medulloblastoma subgroups and used cross-species analysis to compare these models to human medulloblastoma subgroups This study aimed to investigate the cell of origin of Group3 MB using our orthotopical MYC model followed by a novel electroporation approach. Orthotopic cell-lineage specific MYC tumors were generated by enforced Myc expression in P6 GNPs isolated from P0-1 tamoxifen treated [Atoh1-CreER;Trp53fl/-] and [Prom1-CreER;Trp53fl/-] mice followed by cortical implants in immunocompromised mice. These tumors are referred to as Atoh1ER-MYC [dka072-075], Prom1-CreER [dka077-081]. The first Group3 MB models in which tumors developed in situ were generated by electroporation of plasmids containing Myc and dominant negative Trp53 flanked by loxP sites into the fourth ventricle of E13.5 Blbp-Cre [dka081, 087, 089, 090, 091 and blm121], Gad2-IRES-Cre [blm128-130 and blm134] and Ptf1a-Cre [blm135-137] mouse embryos. The gene expression profile of these tumors were compared to our previously published Group3 MB model as well as SHH and WNT models of medulloblastoma. For SHH subgroup medulloblastoma, [dka001-005, 009, 033 and 034] and [dka050-057], spontaneous medulloblastomas from [Cdkn2c-/-; Trp53Fl/Fl; Nestin-Cre] and [Cdkn2c-/-; Ptch1+/-] (Uziel et al.,2005 Genes Dev) were used, respectively. For Group3 medulloblastomas, [dka013-16, 049 and 065-067], in which Myc was overexpressed in Cdkn2c-/-, Trp53-/- cerebellar cells and implanted into the cortices of immunocompromised nude mice prior to tumor isolation. For WNT subgroup medulloblastomas [pgr003, 016 and 066], spontaneously developed tumors from CTNNB1+/lox (ex3); BLBP-Cre; Trp53Fl/Fl (Gibson et al., 2010, Nature) were removed for RNA extraction.

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P53 Promotes Peroxisomal Fatty Acid β-oxidation to Repress Purine metabolism and Mediate Tumor Suppression

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