A5074383844- Cancer Genomics and Diagnostics
- Cancer, Hypoxia, and Metabolism
- Cancer-related Molecular Pathways
- Epigenetics and DNA Methylation
- Glioma Diagnosis and Treatment
- Hedgehog Signaling Pathway Studies
- Colorectal Cancer Treatments and Studies
- Axon Guidance and Neuronal Signaling
- PARP inhibition in cancer therapy
- Cancer Research and Treatments
- Genetic factors in colorectal cancer
- RNA modifications and cancer
- Pharmacogenetics and Drug Metabolism
- Single-cell and spatial transcriptomics
- CAR-T cell therapy research
- Chromosomal and Genetic Variations
- Polyamine Metabolism and Applications
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Cancer Mechanisms and Therapy
- Medical and Biological Sciences
- Genomic variations and chromosomal abnormalities
- Hippo pathway signaling and YAP/TAZ
- Metabolomics and Mass Spectrometry Studies
- Cannabis and Cannabinoid Research
Center for Neuro-Oncology
2023-2025
Dana-Farber Cancer Institute
2020-2025
Harvard University
2021-2025
Broad Institute
2021-2025
Uppsala University
2017-2025
Science for Life Laboratory
2017-2025
Boston University
2022
Abstract The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences 170 pediatric high-grade gliomas and find that truncating increase the stability its phosphatase are clonal driver events 11% Diffuse Midline Gliomas (DMGs) enriched primary pontine tumors. Through development DMG mouse models, show potentiate activity is required for vivo oncogenesis. Finally, apply integrative phosphoproteomic functional genomics assays...
Abstract While the effect of amplification-induced oncogene expression in cancer is known, impact copy-number gains on “bystander” genes less understood. We create a comprehensive map dosage compensation by integrating and copy number profiles from over 8000 tumors The Cancer Genome Atlas cell lines Cell Line Encyclopedia. Additionally, we analyze 17 open reading frame screens to identify toxic cells when overexpressed. Combining these approaches, propose class ‘Amplification-Related Gain Of...
Abstract Functional precision medicine (FPM) aims to optimize patient-specific drug selection based on the unique characteristics of their cancer cells. Recent advancements in high throughput ex vivo profiling have accelerated interest FPM. Here, we present a proof-of-concept study for an integrated experimental system that incorporates treatment response with single-cell gene expression output enabling barcoding several conditions one sequencing experiment. We demonstrate this through...
Inhibitors of murine double minute homolog 2 (MDM2) represent a promising therapeutic approach for the treatment TP53 wild-type glioblastomas (GBMs), reactivating p53 signaling to induce cancer cell death. We conducted surgical window-of-opportunity trial (NCT03107780) MDM2 inhibitor navtemadlin (KRT-232) in 21 patients with recurrent GBM determine achievable drug concentrations within tumor tissues and biological mechanisms response resistance. Participants received at 120 mg ( n = 10) or...
Recent work by the ICGC-PCAWG consortium identified recurrent focal deletions in BRD4 gene, decreasing expression despite increased copy number. We show that these occur context of cyclin E1 amplification breast, ovarian, and endometrial cancers, serve to disrupt regulatory regions gene across isoforms. analyze open reading frame screen data find overexpression long (BRD4-L) short isoform BRD4-S(a) impairs cell growth lines. confirm results OVSAHO ovarian cancer cells, where isoforms...
The contribution of somatic mutations to metastasis colorectal cancers is currently unknown. To find involved in the cancer metastatic process, we performed deep mutational analysis 676 genes 107 stages II IV primary cancer, which half had metastasized. mutation prevalence ephrin (EPH) family tyrosine kinase receptors was 10-fold higher tumors than nonmetastatic cases and preferentially occurred stage III tumors. Mutational analyses situ confirmed expression mutant EPH receptors. enable...
N-Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamine N-acetyltransferase that mainly converts aromatic amines, hydroxylamines, hydrazines. Herein, we demonstrate human also acetylates aliphatic endogenous amines. Metabolomic analysis chemical synthesis revealed increased intracellular concentrations mono- diacetylated spermidine cell lines expressing rapid compared to slow acetylator...
Abstract Cancer chemotherapy targeting frequent loss of heterozygosity events is an attractive concept, since tumor cells may lack enzymatic activities present in normal constitutional cells. To find exploitable targets, we map prevalent genetic polymorphisms to protein structures and identify 45 nsSNVs (non-synonymous small nucleotide variations) near the catalytic sites 17 enzymes frequently lost cancer. For proof select gastrointestinal drug metabolic enzyme NAT2 at 8p22, which colorectal...
Abstract Background Genes in the Ras pathway have somatic mutations at least 60 % of colorectal cancers. Despite activating same pathway, BRAF V600E mutation and prevalent codon 12 13 KRAS all been linked to different clinical outcomes, but molecular mechanisms behind these differences largely remain be clarified. Methods To characterize similarities between common mutations, we used genome editing engineer G12C/D/V G13D cancer cells that had their mutant allele removed subjected them...
// Tatjana Pandzic 1 , Veronica Rendo Jinyeong Lim 2 Chatarina Larsson Jimmy Ivaylo Stoimenov Snehangshu Kundu Muhammad Akhtar Ali Mats Hellström Liqun He Anders M. Lindroth and Tobias Sjöblom Science for Life Laboratory, Department of Immunology, Genetics Pathology, Uppsala University, Uppsala, Sweden Cancer Biomedical Science, National Center Graduate School Policy, Goyang-si, Republic Korea Correspondence to: Sjöblom, email: tobias.sjoblom@igp.uu.se Keywords: colorectal cancer; PRDM2;...
Abstract Therapies targeting somatic bystander genetic events represent a new avenue for cancer treatment. We recently identified subset of colorectal (CRC) patients who are heterozygous wild-type and low activity allele ( NAT2*6 ) but lack the in their tumors due to loss heterozygosity (LOH) at 8p22. These were sensitive treatment with cytotoxic substrate NAT2 (6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine, APA), pointed being therapeutically exploitable vulnerability CRC...
Abstract Chromosomal gains are among the most frequent somatic genetic alterations occurring in cancer. While effect of sustained oncogene expression has been characterized, impact copy-number affecting collaterally-amplified “bystander” genes on cellular fitness remains less understood. To investigate this, we built a comprehensive map dosage compensations across human cancers by integrating and copy number profiles from over 8,000 TCGA tumors CCLE cell lines. Further, analyzed gene...
Loss of heterozygosity (LOH) is a hallmark feature cancer genomes that reduces allelic variation, thereby creating tumor specific vulnerabilities which could be exploited for therapeutic purposes. We previously reported loss drug metabolic arylamine N-acetyltransferase 2 (NAT2) activity following LOH at 8p22 targeted collateral lethality anticancer therapy in colorectal (CRC). Here, we report novel compound CBK034026C exhibits toxicity towards CRC cells with high NAT2 activity. Connectivity...
<h3>Introduction/Background</h3> Loss of heterozygosity (LOH) is a common event driven by genetic instability in cancer cells and large chromosomal losses. As consequence non-cancer gene gets lost as bypass due to its proximity gene. If this was heterozygous state normal cell, tumour cell might become hemi- or homozygous for that change phenotype compared cells. This enable targeting while sparing After our initial proof-of-concept study colorectal with 8p22 loss (Rendo et al., 2020) we...
Abstract Mutations in PPM1D – coding for the phosphatase WIP1 - are present 8 -12% of all Diffuse Midline Glioma (DMG), H3 K27-altered a universally fatal subtype pediatric high-grade tumors. mutations mutually exclusive with TP53 and mainly lead to truncation its C-terminal regulatory domain. Truncated (PPM1Dtr) has increased protein stability impairs p53-dependent DNA Damage Response (DDR) by dephosphorylating numerous targets (e.g p53, H2A.X, CHK1) which contributes oncogenicity. However,...
Abstract p53 pathway reactivation through pharmacologic inhibition of negative regulators was identified as a promising therapeutic strategy for TP53 wild-type (WT) high-grade gliomas, including Diffuse Midline Gliomas (DMGs). Despite widespread theoretical promise, the efficacy MDM2 inhibitors and PPM1D single agents have each been limited by issues, sub-lethal effects on cancer cells innate or emerging resistance leading to tumor progression. We carried out genome-scale CRISPR activating...
Abstract Bone morphogenetic protein 4 (BMP4) has emerged as a potential glioblastoma therapy due to its anti- proliferative effect via SOX2 downregulation and differentiation promotion. However, BMP4 responses vary across within tumors. Our previous data indicate that induces transition mesenchymal-like cell state. Mesenchymal is associated with therapy-resistance tumor recurrence, senescence in cancer. In this study, we investigated BMP4’s induce primary cells, including proneural- clones...
Abstract N ‐Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamine ‐acetyltransferase that mainly converts aromatic amines, hydroxylamines, hydrazines. Herein, we demonstrate human also acetylates aliphatic endogenous amines. Metabolomic analysis chemical synthesis revealed increased intracellular concentrations mono‐ diacetylated spermidine cell lines expressing rapid compared to slow...