A5066083958- Cancer Immunotherapy and Biomarkers
- Cancer Genomics and Diagnostics
- Immunotherapy and Immune Responses
- HIV Research and Treatment
- Cancer-related Molecular Pathways
- Immune cells in cancer
- CAR-T cell therapy research
- Single-cell and spatial transcriptomics
- T-cell and B-cell Immunology
- MicroRNA in disease regulation
- RNA modifications and cancer
- Signaling Pathways in Disease
- Cell Image Analysis Techniques
- CRISPR and Genetic Engineering
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- Cytomegalovirus and herpesvirus research
- Pancreatic and Hepatic Oncology Research
- Phagocytosis and Immune Regulation
- Immune responses and vaccinations
- Calcium signaling and nucleotide metabolism
- Ferroptosis and cancer prognosis
- Cancer, Hypoxia, and Metabolism
- Diet, Metabolism, and Disease
- Lipid metabolism and biosynthesis
University of Pennsylvania
2022-2024
Cancer Research Institute
2023-2024
The Wistar Institute
2022-2023
UPMC Hillman Cancer Center
2023
The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation nucleus. two canonical precursors to nuclear-cytoplasmic compartment are citrate acetate, which processed by ATP-citrate lyase (ACLY) acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It unclear whether other substantial routes nuclear-cytosolic exist. To investigate this, we generated cancer cell lines lacking ACLY ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing,...
The tumor suppressor protein p53 suppresses cancer by regulating processes such as apoptosis, cell cycle arrest, senescence, and ferroptosis, which is an iron-mediated lipid peroxide-induced death pathway. Whereas numerous target genes have been identified, only a few appear to be critical for the suppression of growth. Additionally, while ferroptosis clearly implicated in p53, with roles identified. We previously studied germline missense variants that are hypomorphic or display reduced...
Abstract The p53 tumor suppressor regulates multiple context-dependent suppressive programs. Although is mutated in ~90% of small cell lung cancer (SCLC) tumors, how mediates suppression this context unknown. Here, using a mouse model SCLC which endogenous expression can be conditionally and temporally regulated, we show that tumors maintain requirement for inactivation. However, identify subtype heterogeneity between such reactivation induces senescence subset while others, necrosis. We...
The tumor suppressor
<p>Table S1 and Table S2</p>
<p>Figure S2 shows that the tumor microenvironment in both P47 and S47 mice is comprised of similar proportions subpopulations immune cells with phenotypes.</p>
<div>Abstract<p>The tumor suppressor TP53 is the most frequently mutated gene in cancer and mutationally inactivated fifty percent of sporadic tumors. Inactivating mutations also occur Li Fraumeni syndrome (LFS). In addition to germline LFS that completely inactivate this protein, there are many more mutant forms human populations partially protein: we call these inactivating “hypomorphs”. One hypomorphs a single nucleotide polymorphism (SNP) exists 6-10% Africans 1-2% African...
<p>Table S1 and Table S2</p>
<p>Figure S2 shows that the tumor microenvironment in both P47 and S47 mice is comprised of similar proportions subpopulations immune cells with phenotypes.</p>
<p>Figure S1 shows BMDMs from S47 mice are more anti-inflammatory and polarize towards a M2 phenotype following IL-4 stimulation.</p>
<div><p>The tumor suppressor <i>TP53</i> is the most frequently mutated gene in cancer and mutationally inactivated 50% of sporadic tumors. Inactivating mutations also occur Li Fraumeni syndrome (LFS). In addition to germline LFS that completely inactivate this protein, there are many more mutant forms human populations partially protein: we call these inactivating “hypomorphs.” One hypomorphs a SNP exists 6%–10% Africans 1%–2% African Americans, which changes proline...
<p>Figure S1 shows BMDMs from S47 mice are more anti-inflammatory and polarize towards a M2 phenotype following IL-4 stimulation.</p>
<p>Figure S1 shows BMDMs from S47 mice are more anti-inflammatory and polarize towards a M2 phenotype following IL-4 stimulation.</p>
<p>S47 mice are less responsive to PD-L1 blockade therapy. <b>A,</b> Tumor growth curves for P47 and S47 treated with rat IgG2b isotype control antibody or anti-PD-L1 following MC38 cell injections. <i>n</i> = 7 control; 5 9 anti-PD-L1; 10 anti-PD-L1. <b>B,</b> Graph showing the frequency of palpable tumors in receiving antibody. <b>C</b> <b>D,</b> Individual tumor each mouse Statistics were derived from Wilcoxon rank-sum...
<p>S47-derived T cells display a steady-state deficit in effector T-cell function after stimulation. RBC-depleted splenocytes from either S47 or P47 mice were stimulated with PMA/Ionomycin, Concanavalin A, anti-CD3/CD28 Dynabeads, then assayed for cytolytic markers and cytokine production via multiparametric flow cytometry. Values normalized to negative control wells receiving no Data are derived four independent experiments. <b>A–C,</b> Differences...
<p>S47-derived T cells display a steady-state deficit in effector T-cell function after stimulation. RBC-depleted splenocytes from either S47 or P47 mice were stimulated with PMA/Ionomycin, Concanavalin A, anti-CD3/CD28 Dynabeads, then assayed for cytolytic markers and cytokine production via multiparametric flow cytometry. Values normalized to negative control wells receiving no Data are derived four independent experiments. <b>A–C,</b> Differences...
<p>Differences in memory T-cell formation and chemokine receptor usage S47 mice. Splenocytes derived from non–tumor-bearing, male P47 mice between the ages of 6 10 weeks were analyzed by flow cytometry for differences baseline phenotypes. Data are five independent cohorts (<i>n</i> = 27 S47, <i>n</i> 26 P47), all panels incorporate multiple cohorts. <b>A</b> <b>B,</b> Frequencies total (CD44<sup>+</sup>) central...
<p>S47 mice are less responsive to PD-L1 blockade therapy. <b>A,</b> Tumor growth curves for P47 and S47 treated with rat IgG2b isotype control antibody or anti-PD-L1 following MC38 cell injections. <i>n</i> = 7 control; 5 9 anti-PD-L1; 10 anti-PD-L1. <b>B,</b> Graph showing the frequency of palpable tumors in receiving antibody. <b>C</b> <b>D,</b> Individual tumor each mouse Statistics were derived from Wilcoxon rank-sum...
<p>Table S1 and Table S2</p>
<p>Tumor-bearing S47 mice harbor more immunosuppressive splenic immune cell profiles. <b>A,</b> Flow cytometry analyses on splenocytes from TBM for percent positive MDSCs in P47 and mice, respectively. Bar graph right shows the out of total CD45<sup>+</sup> cells. <i>n</i> = 5 per group. <b>B,</b> indicated activation markers macrophages spleen. Histograms top show mean fluorescent intensity (MFI) MHC I histograms bottom MFI CD86. The red...
<p>The tumor growth advantage in S47 mice is abolished following CD8<sup>+</sup> T-cell depletion. <b>A,</b> Illustration of the experimental approach. Replicate P47 and were injected subcutaneously with 1 × 10<sup>6</sup> MC38 cells. At day 19, spleens tumors from harvested analyzed by flow cytometry. <b>B,</b> Tumor curves for <i>n</i> = 5 per group. Linear mixed model used statistical analysis. **, <i>P</i> <...
<p>Tumor-infiltrating T cells in S47 mice display uniquely elevated transcription factor profiles. Tumors and spleens were harvested 21 days after injection of MC38 analyzed for expression by intranuclear flow cytometry. <b>A,</b> The percentage proliferating (Ki67<sup>+</sup>) TILs P47 mice. <b>B,</b> Frequency Eomes<sup>+</sup> or Tbet<sup>+</sup> <b>C,</b> expressing mTOR phosphorylated at serine 2448...
<p>Figure S1 shows BMDMs from S47 mice are more anti-inflammatory and polarize towards a M2 phenotype following IL-4 stimulation.</p>
<p>Tumor-infiltrating T cells in S47 mice display uniquely elevated transcription factor profiles. Tumors and spleens were harvested 21 days after injection of MC38 analyzed for expression by intranuclear flow cytometry. <b>A,</b> The percentage proliferating (Ki67<sup>+</sup>) TILs P47 mice. <b>B,</b> Frequency Eomes<sup>+</sup> or Tbet<sup>+</sup> <b>C,</b> expressing mTOR phosphorylated at serine 2448...