TP53 R172H

Our study elucidates the mutant-specific impact of p53R270H and p53R172H on metabolism of PDAC cancer cells, highlighting the need to shift from viewing p53 mutant variants as a homogeneous group of entities to a systematic assessment of each specific p53 mutant protein. Moreover, our finding underscores the importance of further exploring the significance of p53 mutant proteins using models that more accurately reflect tumor ecology.

Multiplex immunohistochemistry demonstrated increased M2-polarized macrophages proximal to nerves in SEMA3D-expressing human PDA tissue. This study suggests that altered SEMA3D expression leads to an acquisition of cancer-promoting functions, and nerve-derived SEMA3D is "hijacked" by PDA cells to support growth and metastasis in a KRASMUT-dependent manner.

p53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia.

p53 R172H occupies these enhancers in an NF-κB-pathway-dependent manner, suggesting NF-κB's role in recruiting p53 R172H to the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC.

The study demonstrated the role of EHF in the recruitment of CXCR2+neutrophils and the promising role of Nifurtimox in sensitizing pancreatic cancer to chemotherapy and immunotherapy.

Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6, which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death.

Blockade of the CCL9-CCR1 axis could limit G-MDSC migration, and depletion of Ly6G-positive cells could sensitize tumors to the combination of TH-302 and anti-VEGFR-2 with ICB. Together, these data suggest that pancreatic tumors modulate G-MDSC migration as an adaptive response to vascular normalization, and that these immunosuppressive myeloid cells act in a setting of persistent hypoxia to maintain adaptive immune resistance.

Successful engraftment and CreER activity, induced by a 2-week period of Tamoxifen chow, were confirmed by flow cytometry...We further examined the levels of p53 induced by nutlin-3a (an MDM2 inhibitor) in edited BM cells from three groups of mice and found that Trp53 editing leads to a reduction in p53 levels and prevents the loss of viability in response to MDM2 inhibition...These mouse models of secondary AML are valuable for testing new therapies targeting disease initiating stem cells. Moreover, our models represent the distinct stages of MPN progression, offering a platform to evaluate preventive and therapeutic interventions at various stages of this disease.

Patients were treated with a variety of PARPi including Olaparib (n=48), Talazoparib (n=33), Rucaparib (n = 13) and Niraparib (n = 6.) Of the 418 patients, 45 individuals harbored an HRD germline mutation...The percentage of Trp53 R172H cells in the blood was measured by flow cytometry at baseline (6 weeks after transplantation) and after treatment with vehicle alone, Talazoparib or Olaparib daily, or cisplatin weekly, for 4 weeks...Indeed, our data suggest the opposite, with the fitness advantage of DDR gene-mutated HSPCs lost in cells with a heterozygous Brca1-mutations. These data suggest that PARPi therapy may have less of an impact on leukemia risk compared to carboplatin and in fact may show synergistic effects with HRD in blocking the competitive advantage of DDR CH during genotoxic stress.

This data demonstrates the importance of age in the development of p53 mutant myeloid malignancies, and that p53 mutations in adult HSCs lead to the development of myeloid, but not lymphoid malignancies, highlighting the different mechanisms underlying the development of these types of malignancies, and suggest potential preventative or therapeutic strategies for TP53-mutant AML.

Furthermore, we examined the interplay between p53R172H and NF-kB and found that the p53R172H physically interacts with the NF-kB subunit RelA and facilitates its nuclear translocation. Conclusions Overall, we characterize how a common p53 mutation in PDAC co-opts non-coding regulatory DNA to augment the expression of selective chemokine genes and establishes an immunosuppressive TME to shield the therapeutic benefits of ICIs.

The proteasome inhibitor bortezomib stabilized NFκB inhibitory protein IκBα reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergizes with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.

Inhibition of Brd4 not only reduces tumor invasion and lung metastasis, but also reduces circulating Csf-1 levels. Overall, our results establish a novel p53-R172H-dependent Brd4-Csf-1 axis that promotes ESCC lung metastasis, and suggest avenues for therapeutic strategies for this difficult-to-treat disease.

These findings demonstrate that syngeneic tumors bearing the TP53R172H gain-of-function mutation modulate the TIME to evade tumor immunity, leading to tumor progression and decreased survival.

Downstream analyses revealed that deletion of mutant Trp53 activated the cyclic GMP-AMP Synthase-Stimulator of Interferon Genes pathway but did not cause apoptosis implicating other mechanisms of tumor regression. Furthermore, we determined that only tumors with stable mutant p53 are dependent on mutant p53 for growth.

Additionally, analyses of p53R248W ChIP peaks showed enrichment of KLF15 motifs in human osteoblasts. Taken together, these data identify unique mechanisms of action of the structural and contact mutants of p53.

TNFR2 inhibition disrupts this circuitry and improves sensitivity to chemotherapy in vivo. Our results uncover cancer cell-neutrophil crosstalk in which context-dependent TNF signaling amplifies stromal inflammation and immune tolerance to promote therapeutic resistance in PDAC.

Furthermore, TRIM21 was frequently downregulated in some human cancers, including colorectal and breast cancers, and low TRIM21 expression was associated with poor prognosis in patients with cancers carrying mutp53. Our results revealed a critical mechanism underlying mutp53 accumulation in cancers, and also uncovered an important tumor-suppressive function of TRIM21 and its mechanism in cancers carrying mutp53.

We have demonstrated novel roles and mechanisms of mutant p53-dependent CSF1-CSF1R signaling pathway in fostering ESCC tumor invasion and lung metastasis that may be applicable to other SCCs. We believe this can open up new avenues for therapeutic applications.

Furthermore, Trp53R172H/flox; Ptenflox/flox organoids showed higher engraftment rate in immunocompetent mice with less infiltration of CD8+ cells compared with Trp53flox/flox; Ptenflox/flox organoids, suggesting that gain of function of mutant Trp53 may affect immune microenvironment. Our data illustrates the usefulness of clinically relevant syngeneic bladder cancer mouse model from GEM-derived organoids for the research of tumor immunity.

Our findings collectively demonstrate that the mutant TP53 GOF mutation modulates the tumor immune landscape and is associated with reduced overall survival in patients with OSCC.

The orthotopic implantation using COLO357:10-03-P CAFs (1:1) in athymic nude mice and KRasG12D; TP53R172H; Pdx-1-Cre (KPC) homograft in C57BL/6 mice was performed to evaluate the effect of bosentan (10 mg/Kg/daily/IP) on gemcitabine (50 mg/Kg/bi-weekly/IP) + nab-paclitaxel (60 mg/Kg/bi-weekly/iv) (Gem + Nab-P) efficacy. Our data suggest that bosentan treatment enhances the therapeutic effect of PDAC chemotherapy. Further analysis will elucidate the mechanistic underpinnings of improved treatment response. Overall, targeting the ET-axis could be a potential strategy for PDAC therapy.

However, this same result was not observed in CCR4Y331X, which is commonly associated with TP53 mutation in PTCL-GATA3 clinical cases, suggesting these mutations can increase in TCR signaling to enhance lymphomagenesis in the absence of mutant TP53. These findings indicate that the occurrence of these lesions activates divergent pathways, resulting in T-cell transformation towards the TH2 phenotype.

We generated a traceable Tamoxifen-inducible conditional somatic TP53R172H mutant mouse model to monitor and track the expansion of p53 mutant myeloid cells over the course of therapy with MDM2i. Overall, these data indicate that the prior existing TP53-mutant subclones are expanded upon idasanutlin treatment without being transformed. Therefore, monitoring of TP53-mutant subclones during the course of treatment is warranted.

Conclusions IRE can induce local tumor regression and generate neoantigen-specific immune responses. Addition of CD40Ab to IRE improved neoantigen recognition, thereby generating a strong systemic anti-tumor T-cell response that inhibited metastatic disease progression.

These new orthotopic mouse models demonstrate that each of the isogenic hotspot p53 amino acid mutations studied (R172H and R245W, the mouse equivalents of human R175H and R248W respectively), drive unique cellular changes affecting pathways of proliferation and immunity. Our findings support the hypothesis that individual p53 mutations confer their own particular oncogenic gain of function in prostate cancer.

Material and Methods 5×10 6 cells of ID8; ID8 p53 -/-, ID8 p53 -/- R175H and ID8 p53 -/- R273H were injected into C57BL/6 female mice, followed by 6 weeks of injections with anti-AREG (AR37) and anti-PD-L1 (Avelumab) 400µg/ mouse, twice a week...Conclusion Elucidating the varied response of EOC to monotherapies, we aim at evaluating an anti-AREG antibody in conjunction with PD-L1 therapy for synergistic effect. Our aim is to develop a safe and efficacious combinatorial therapy addressing the complexity of AREG and PD-L1 expression in EOC onset and progression.

Further mechanistic study elucidated that p53 can modulate expression by cancer cells of Mult-1 and H60a, which are activating and inhibitory ligands for NKG2D receptors of NK cells, respectively, to enhance immune surveillance against cancer. Our findings demonstrate that wt p53 is requisite for NK cell-based immune recognition and elimination of cancerous cells, and perhaps more importantly, that p53 missense mutant presence in cancer cells impairs NK cell-attributable responses, thus veiling cancerous cells from host immunity and enabling cancer progression.

Conclusion Diffuse type gastric cancer forms tumor progression circuit with angiogenesis and fibrosis by expressingDGC tumors carrying mutations in Cdh1 and Tgfbr2 genes express high levels of CD38 and Lrg1, which contribute to tumor invasion by remodeling tumor microenvironment. Treatment targeting these genes could be an option for personalized medicine against DGCs carrying these gene mutations, suggesting the possibility that CD38 and CD105 are new therapeutic target of DGC.

Transcriptomic analyses of p53R172H/K-RasG12D GEMM-derived tumors showed evidence of high molecular homology with human RMS. Finally, pre-clinical use of these murine RMS lines showed similar therapeutic responsiveness to chemotherapy and targeted therapies as human RMS cell lines.

Then, we examined the chemosensitivity with cisplatin through clonogenic assays...Preliminary results revealed a significant tumor response only to STING agonist (c-di-GMP) which activates the innate and adaptive immune response. Therefore, we were able to characterize all three cell lines and established a new mouse model of cSCC as a relevant platform for immunotherapy studies.