Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion

Schulz-Heddergott, Ramona; Stark, Nadine; Edmunds, Shelley J.; Li, Jinyu; Conradi, Lena‐Christin; Bohnenberger, Hanibal; Ceteci, Fatih; Greten, Florian R.; Dobbelstein, Matthias; Moll, Ute M.

doi:10.1016/j.ccell.2018.07.004

Cited by 166 publications

(181 citation statements)

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“…Stabilization of missense mutant p53 (mutp53) proteins specifically in tumor but not normal cells is a key feature and prerequisite of GOF 16, 42 . Since p53LOH is a critical prerequisite for mutp53 stabilization in sarcomas and breast cancer 41 , we examined mutp53 stabilization before and after p53LOH in the colorectal AOM/DSS model 9 . Briefly, we combined the humanized GOF TP53 R248Q allele (short ‘p53 Q ’) with either p53 wildtype (WT, ‘+’) or knock-out (‘-’) alleles and determined the p53LOH effect on mutp53 levels (Figures S1A-B).…”

Section: Resultsmentioning

confidence: 99%

“…Mutp53 stabilization is a critical prerequisite for mutp53 GOF 9 . Indeed, all p53LOH mice exhibited stabilized mutp53, in sharp contrast to mice with a retained WTp53 allele (Figure 1F).…”

Section: Resultsmentioning

confidence: 99%

“…The vast majority of TP53 alterations are missense mutations (mutp53) with hotspot codons R175, G245, R248, R273 and R282 11-13 . In addition to loss-of-WTp53 function (LOF), some, especially hotspot, mutp53 alleles gain broad tumorigenic gain-of-function (GOF) and actively promote aggressive cancer progression in vivo 9, 14-20 . Some GOF mutants acquire allele-specific functions, not necessarily shared by other mutants 3, 9, 21-26 .…”

Section: Introductionmentioning

confidence: 99%

“…p53LOH is a critical prerequisite for mutp53 stabilization in tumors. Heterozygous tumors rarely if ever stabilize p53 in vivo 9, 19, 41, 42 . Importantly, the majority of human mutp53 tumors have undergone p53LOH 43-47 .…”

Section: Introductionmentioning

confidence: 99%

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Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

Sener

Stender

Klemke

et al. 2020

Preprint

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HIGHLIGHTS 14 15• heterozygous p53 R248Q/+ tumors retain p53 transcriptional activity in a mouse model of 16 colorectal cancer (CRC) 17• wildtype p53 actively represses the tumor-promoting HSF1-regulated chaperone system 18 and proteotoxic stress response 19• the repressive WTp53 -HSF1 axis creates a selective pressure for WTp53 loss-of-20 heterozygosity in CRC tumors 21• p53 loss-of-heterozygosity enables stabilization of the gain-of-function p53 R248Q mutant 22 protein which in turn enables CRC invasion 23 24 25 26 27 28 29 30 2 31 Abstract 32A prerequisite for gain-of-function (GOF) p53 missense mutants (mutp53) is protein 33 stabilization. Moreover, a prerequisite for mutp53 stabilization is loss of the remaining wildtype 34 (WT) p53 allele (loss-of-heterozygosity, p53LOH) in mutp53/+ tumors. Thus, GOF, mutp53 35 stabilization and p53LOH are strictly linked. However, the driving force for p53LOH is unknown. 36Typically, heterozygous tumors are an instable transition state. Here we identify the repressive 37WTp53-HSF1 axis as the driver of p53LOH. 38We find that the WTp53 allele in AOM/DSS-induced colorectal tumors (CRC) of p53 R248Q/+ mice 39 retains its haploid transcriptional activity. Notably, WTp53 represses heat-shock factor 1 (HSF1) 40 activity, the master transcription factor of the proteotoxic stress defense response (HSR) that is 41 ubiquitously and constitutively activated in cancer tissues. HSR is critical for stabilizing 42 oncogenic proteins including mutp53. WTp53-retaining murine CRC tumors and tumor-derived 43 organoids and human CRC cells all suppress the tumor-promoting HSF1 transcriptional 44 program. 45Mechanistically, the retained WTp53 allele activates CDKN1A/p21, leading to cell cycle 46 inhibition and suppression of the E2F target gene MLK3. MLK3 links cell cycle to the MAPK 47 stress pathway to activate the HSR response. We show that in p53 R248Q/+ tumors WTp53 48 activation by constitutive stress (emanating from proliferative/metabolic stresses and genomic 49 instability) represses MLK3, consequently inactivating the MAPK-HSF1 response necessary to 50 ensure tumor survival. This creates strong selection pressure for p53LOH which eliminates the 51 repressive WTp53-HSF1 axis and unleashes the tumor-promoting HSF1 functions, inducing 52 mutp53 stabilization and enabling invasion. 53 54 Keywords 55 mutp53, HSF1, Hsp90, Hsp70, CDK4, MLK3, MAPK, AOM/DSS, colorectal cancer, organoids, 56 Idasanutlin 57 58 59 60 RESULTS 101 p53LOH is a prerequisite for mutp53 stabilization and invasion in colorectal cancer 102Stabilization of missense mutant p53 (mutp53) proteins specifically in tumor but not normal cells 103 is a key feature and prerequisite of GOF 16, 42 . Since p53LOH is a critical prerequisite for mutp53 104 stabilization in sarcomas and breast cancer 41 , we examined mutp53 stabilization before and 105 after p53LOH in the colorectal AOM/DSS model 9 . Briefly, we combined the humanized GOF 106

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Section: Resultsmentioning

confidence: 99%

“…Mutp53 stabilization is a critical prerequisite for mutp53 GOF 9 . Indeed, all p53LOH mice exhibited stabilized mutp53, in sharp contrast to mice with a retained WTp53 allele (Figure 1F).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

Sener

Stender

Klemke

et al. 2020

Preprint

Self Cite

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“…3B). A known GOF mutation in TP53 (R248Q)(42) was detected in Kasumi-1 AML cells(Supplemental Fig. 3B).…”

mentioning

confidence: 98%

TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

Lai

Vadakekolathu

Reeder

et al. 2020

Preprint

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Purpose: Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37-46% of acute myeloid leukemia (AML) cases with adverse risk cytogenetics and are associated with primary induction failure (PIF), high risk of relapse and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53 mutated AML and to determine whether TP53 abnormalities identify a patient subgroup that may benefit from T-cell targeting immunotherapy approaches. Experimental Design: The NanoString Pan-Cancer IO 360™ assay was used for the immune transcriptomic analysis of 64 diagnostic bone marrow (BM) samples from adults with TP53 mutated AML (n=42) or TP53 wild type AML (n=22), and 35 BM samples from heavily pretreated patients with relapsed/refractory (R/R) AML (11 cases with TP53 mutations and/or 17p deletion with genomic loss of TP53) who received immunotherapy with flotetuzumab, an investigational CD123×CD3 bispecific DART ® molecule (NCT02152956). In silico data series included The Cancer Genome Atlas (TCGA) cohort and a Dutch-Belgian Cooperative Trial Group for Hematology-Oncology (HOVON) cohort. Results: All TCGA cases with TP53 mutations (n=13) expressed higher levels of negative immune checkpoints, inflammatory chemokines, interferon (IFN)-γ-inducible molecules, and had a higher tumor inflammation signature (TIS) score, compared with TCGA cases with other riskdefining molecular lesions. The comparison between TP53 mutated and TP53 wild type primary BM samples showed higher expression of IFNG, FoxP3, immune checkpoints and markers of exhaustion and senescence in the former cohort and allowed the computation of a 34-gene immune classifier prognostic for overall survival. In vitro modeling experiments with AML cell lines showed heightened expression of IFN-γ and inflammation pathway genes in KG-1 cells (loss-of-function mutation of TP53) compared with Kasumi-1 cells (gain-of-function mutation of TP53). Finally, 5 out of 11 (45.5%) patients with R/R AML and TP53 abnormalities showed evidence of anti-leukemic activity of flotetuzumab immunotherapy and had higher TIS, FoxP3, CD8 T-cell abundance, inflammatory chemokine and PD1 gene expression scores at baseline compared with non-responders. Conclusions:This study provides evidence for a correlation between IFN-γ-dominant immune subtypes and TP53 abnormalities. The anti-leukemic activity with flotetuzumab encourages further study of this immunotherapeutic approach in this patient subgroup.further studies of T-cell targeting immunotherapeutic approaches in patients with TP53 mutations.

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Bispecific, Exosome‐Mimetic Lipid Nanoparticles Facilitate Dual siRNAs for Synergistic Therapy against Pancreatic Cancer

Wang,

Zhang,

Wang

et al. 2024

Adv Funct Materials

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While RNA therapeutics hold great promise for combating pancreatic ductal adenocarcinoma (PDAC), the limited therapy outcome due to the insufficient delivery efficiency of vehicles and inadequate innate therapeutic potency for single siRNA hinders the broader application. Herein, report bispecific, exosome‐mimetic lipid nanoparticles (EM‐LNPs) carrying high loads of siKras and siTP53, which can efficiently overcome layers of barriers to accumulate cytoplasm in vitro and in vivo and achieve synergistic treatment for PDAC tumors. EM‐LNPs inherit features of synthetic LNPs and the protein characteristics of exosomes with outer CD47 proteins, membrane‐inserted integrin α6β4, and connexin 43. The siRNAs‐loaded EM‐LNPs can efficiently evade the host immune clearance in the circulation, considerably accumulate and penetrate dense tumors, and simultaneously target EGFR/VEGF of PDAC cells, following leakage into the cytoplasm. The intracellular siKras and siTP53 achieved synergistic therapeutic effects for PDAC cells with as high as 20 times enhancement in vitro and 3.5 times increase in vivo, significantly suppressed xenograft PDAC tumors, considerably reduced lung metastasis, and vastly extended mice survival at a low injection dose. These results explore an approach for delivering multiple gene cargoes to dense PDAC tumors for synergistic therapeutics.

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Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion

Cited by 166 publications

References 50 publications

Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

Bispecific, Exosome‐Mimetic Lipid Nanoparticles Facilitate Dual siRNAs for Synergistic Therapy against Pancreatic Cancer

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