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  1. AU="Teh, Selina Shiqing K"
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  1. Article: Islands of genomic stability in the face of genetically unstable metastatic cancer.

    Bowland, Kirsten / Lai, Jiaying / Skaist, Alyza / Zhang, Yan / Teh, Selina Shiqing K / Roberts, Nicholas J / Thompson, Elizabeth / Wheelan, Sarah J / Hruban, Ralph H / Karchin, Rachel / Iacobuzio-Donahue, Christine A / Eshleman, James R

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Introduction: Metastatic cancer affects millions of people worldwide annually and is the leading cause of cancer-related deaths. Most patients with metastatic disease are not eligible for surgical resection, and current therapeutic regimens have varying ...

    Abstract Introduction: Metastatic cancer affects millions of people worldwide annually and is the leading cause of cancer-related deaths. Most patients with metastatic disease are not eligible for surgical resection, and current therapeutic regimens have varying success rates, some with 5-year survival rates below 5%. Here we test the hypothesis that metastatic cancer can be genetically targeted by exploiting single base substitution mutations unique to individual cells that occur as part of normal aging prior to transformation. These mutations are targetable because ~10% of them form novel tumor-specific "NGG" protospacer adjacent motif (PAM) sites targetable by CRISPR-Cas9.
    Methods: Whole genome sequencing was performed on five rapid autopsy cases of patient-matched primary tumor, normal and metastatic tissue from pancreatic ductal adenocarcinoma decedents. CRISPR-Cas9 PAM targets were determined by bioinformatic tumor-normal subtraction for each patient and verified in metastatic samples by high-depth capture-based sequencing.
    Results: We found that 90% of PAM targets were maintained between primary carcinomas and metastases overall. We identified rules that predict PAM loss or retention, where PAMs located in heterozygous regions in the primary tumor can be lost in metastases (private LOH), but PAMs occurring in regions of loss of heterozygosity (LOH) in the primary tumor were universally conserved in metastases.
    Conclusions: Regions of truncal LOH are strongly retained in the presence of genetic instability, and therefore represent genetic vulnerabilities in pancreatic adenocarcinomas. A CRISPR-based gene therapy approach targeting these regions may be a novel way to genetically target metastatic cancer.
    Language English
    Publishing date 2024-01-29
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.26.577508
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Mechanism of delayed cell death following simultaneous CRISPR-Cas9 targeting in pancreatic cancers.

    Teh, Selina Shiqing K / Halper-Stromberg, Eitan / Morsberger, Laura / Bennett, Alexis / Bowland, Kirsten / Skaist, Alyza / Cai, Fidel / Liang, Hong / Hruban, Ralph H / Roberts, Nicholas J / Scharpf, Robert B / Zou, Ying S / Eshleman, James R

    bioRxiv : the preprint server for biology

    2023  

    Abstract: When we transduced pancreatic cancers with sgRNAs that targeted 2-16 target sites in the human genome, we found that increasing the number of CRISPR-Cas9 target sites produced greater cytotoxicity, with >99% growth inhibition observed by targeting only ... ...

    Abstract When we transduced pancreatic cancers with sgRNAs that targeted 2-16 target sites in the human genome, we found that increasing the number of CRISPR-Cas9 target sites produced greater cytotoxicity, with >99% growth inhibition observed by targeting only 12 sites. However, cell death was delayed by 2-3 weeks after sgRNA transduction, in contrast to the repair of double strand DNA breaks (DSBs) that happened within 3 days after transduction. To explain this discrepancy, we used both cytogenetics and whole genome sequencing to interrogate the genome. We first detected chromatid and chromosome breaks, followed by radial formations, dicentric, ring chromosomes, and other chromosomal aberrations that peaked at 14 days after transduction. Structural variants (SVs) were detected at sites that were directly targeted by CRISPR-Cas9, including SVs generated from two sites that were targeted, but the vast majority of SVs (89.4%) were detected elsewhere in the genome that arose later than those directly targeted. Cells also underwent polyploidization that peaked at day 10 as detected by XY FISH assay, and ultimately died via apoptosis. Overall, we found that the simultaneous DSBs induced by CRISPR-Cas9 in pancreatic cancers caused chromosomal instability and polyploidization that ultimately led to delayed cell death.
    Language English
    Publishing date 2023-04-05
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.03.535384
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: CRISPR-Cas9 for selective targeting of somatic mutations in pancreatic cancers.

    Teh, Selina Shiqing K / Bowland, Kirsten / Bennett, Alexis / Halper-Stromberg, Eitan / Skaist, Alyza / Tang, Jacqueline / Cai, Fidel / Macoretta, Antonella / Liang, Hong / Kamiyama, Hirohiko / Wheelan, Sarah / Lin, Ming-Tseh / Hruban, Ralph H / Scharpf, Robert B / Roberts, Nicholas J / Eshleman, James R

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Somatic mutations are desirable targets for selective elimination of cancer, yet most are found within the noncoding regions. We propose a novel, cancer-specific killing approach using CRISPR-Cas9 which exploits the requirement of a protospacer adjacent ... ...

    Abstract Somatic mutations are desirable targets for selective elimination of cancer, yet most are found within the noncoding regions. We propose a novel, cancer-specific killing approach using CRISPR-Cas9 which exploits the requirement of a protospacer adjacent motif (PAM) for Cas9 activity. Through whole genome sequencing (WGS) of paired tumor minus normal (T-N) samples from three pancreatic cancer patients (Panc480, Panc504, and Panc1002), we identified an average of 417 somatic PAMs per tumor produced from single base substitutions. We analyzed 591 paired T-N samples from The International Cancer Genome Consortium and discovered medians of ~455 somatic PAMs per tumor in pancreatic, ~2800 in lung, and ~3200 in esophageal cancer cohorts. Finally, we demonstrated >80% selective cell death of two targeted pancreatic cancer cell lines in co-cultures using 4-9 sgRNAs, targeting noncoding regions, designed from the somatic PAM discovery approach. We also showed no off-target activity from these tumor-specific sgRNAs through WGS.
    Language English
    Publishing date 2023-10-10
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.15.537042
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Menin regulates the serine biosynthetic pathway in Ewing sarcoma.

    Svoboda, Laurie K / Teh, Selina Shiqing K / Sud, Sudha / Kerk, Samuel / Zebolsky, Aaron / Treichel, Sydney / Thomas, Dafydd / Halbrook, Christopher J / Lee, Ho-Joon / Kremer, Daniel / Zhang, Li / Klossowski, Szymon / Bankhead, Armand R / Magnuson, Brian / Ljungman, Mats / Cierpicki, Tomasz / Grembecka, Jolanta / Lyssiotis, Costas A / Lawlor, Elizabeth R

    The Journal of pathology

    2018  Volume 245, Issue 3, Page(s) 324–336

    Abstract: Developmental transcription programs are epigenetically regulated by multi-protein complexes, including the menin- and MLL-containing trithorax (TrxG) complexes, which promote gene transcription by depositing the H3K4me3 activating mark at target gene ... ...

    Abstract Developmental transcription programs are epigenetically regulated by multi-protein complexes, including the menin- and MLL-containing trithorax (TrxG) complexes, which promote gene transcription by depositing the H3K4me3 activating mark at target gene promoters. We recently reported that in Ewing sarcoma, MLL1 (lysine methyltransferase 2A, KMT2A) and menin are overexpressed and function as oncogenes. Small molecule inhibition of the menin-MLL interaction leads to loss of menin and MLL1 protein expression, and to inhibition of growth and tumorigenicity. Here, we have investigated the mechanistic basis of menin-MLL-mediated oncogenic activity in Ewing sarcoma. Bromouridine sequencing (Bru-seq) was performed to identify changes in nascent gene transcription in Ewing sarcoma cells, following exposure to the menin-MLL interaction inhibitor MI-503. Menin-MLL inhibition resulted in early and widespread reprogramming of metabolic processes. In particular, the serine biosynthetic pathway (SSP) was the pathway most significantly affected by MI-503 treatment. Baseline expression of SSP genes and proteins (PHGDH, PSAT1, and PSPH), and metabolic flux through the SSP were confirmed to be high in Ewing sarcoma. In addition, inhibition of PHGDH resulted in reduced cell proliferation, viability, and tumor growth in vivo, revealing a key dependency of Ewing sarcoma on the SSP. Loss of function studies validated a mechanistic link between menin and the SSP. Specifically, inhibition of menin resulted in diminished expression of SSP genes, reduced H3K4me3 enrichment at the PHGDH promoter, and complete abrogation of de novo serine and glycine biosynthesis, as demonstrated by metabolic tracing studies with
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Bone Neoplasms/drug therapy ; Bone Neoplasms/genetics ; Bone Neoplasms/metabolism ; Bone Neoplasms/pathology ; Cell Line, Tumor ; Cell Proliferation ; Energy Metabolism/drug effects ; Energy Metabolism/genetics ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Humans ; Male ; Mice, Nude ; Myeloid-Lymphoid Leukemia Protein/genetics ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Phosphoglycerate Dehydrogenase/genetics ; Phosphoglycerate Dehydrogenase/metabolism ; Phosphoric Monoester Hydrolases/genetics ; Phosphoric Monoester Hydrolases/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Sarcoma, Ewing/drug therapy ; Sarcoma, Ewing/genetics ; Sarcoma, Ewing/metabolism ; Sarcoma, Ewing/pathology ; Serine/biosynthesis ; Signal Transduction ; Transaminases/genetics ; Transaminases/metabolism ; Tumor Burden ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; KMT2A protein, human ; MEN1 protein, human ; Proto-Oncogene Proteins ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Serine (452VLY9402) ; Phosphoglycerate Dehydrogenase (EC 1.1.1.95) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Transaminases (EC 2.6.1.-) ; phosphoserine aminotransferase (EC 2.6.1.52) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; phosphoserine phosphatase (EC 3.1.3.3)
    Language English
    Publishing date 2018-05-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3119-7
    ISSN 1096-9896 ; 0022-3417
    ISSN (online) 1096-9896
    ISSN 0022-3417
    DOI 10.1002/path.5085
    Database MEDical Literature Analysis and Retrieval System OnLINE

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