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  1. AU="Bowland, Kirsten"
  2. AU="Seri Hong"
  3. AU=Dumontet Charles
  4. AU="Folkerts, Gert"
  5. AU="Romero-Alonso, M Mercedes"
  6. AU="Griego, Danielle"
  7. AU="Guedes-Guedes, Isabel"
  8. AU="Xiaoli Chang"
  9. AU="Jang, Joonseong"
  10. AU="Sergio Lafuente-Arroyo"
  11. AU="Löppönen, Heikki"
  12. AU="Santos, Maria Leonor"
  13. AU=Saluja Bharat
  14. AU="Nezhadi, Akram"
  15. AU=Dhar Debojyoti
  16. AU="Chandrappa S"
  17. AU="Cole, Kevin"
  18. AU=De Ceukelaire Wim
  19. AU=Tomatis L
  20. AU=Chandra Sharad
  21. AU="Mishra, Malvika"
  22. AU="Bruggemann, Kira"
  23. AU="Miura, Tanya A."
  24. AU="Kobeasy, Mohamed I."
  25. AU="Sonthonnax, Florian" AU="Sonthonnax, Florian"
  26. AU="Wang, Rongzu"

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  1. Artikel: 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.
    Sprache Englisch
    Erscheinungsdatum 2024-01-29
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2024.01.26.577508
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: 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.
    Sprache Englisch
    Erscheinungsdatum 2023-04-05
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.04.03.535384
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: 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.
    Sprache Englisch
    Erscheinungsdatum 2023-10-10
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.04.15.537042
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.

    Zhang, Yuxiang / Remillard, David / Onubogu, Ugoma / Karakyriakou, Barbara / Asiaban, Joshua N / Ramos, Anissa R / Bowland, Kirsten / Bishop, Timothy R / Barta, Paige A / Nance, Stephanie / Durbin, Adam D / Ott, Christopher J / Janiszewska, Michalina / Cravatt, Benjamin F / Erb, Michael A

    Nature structural & molecular biology

    2023  Band 30, Heft 8, Seite(n) 1160–1171

    Abstract: Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we ... ...

    Abstract Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we unveil a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2, wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal deletions that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic disruption or dTAG-mediated degradation, we show that targeting HDAC2 suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2-NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders that could leverage HDAC1/2 synthetic lethality to target NuRD vulnerabilities. Altogether, we identify HDAC1/2 collateral synthetic lethality as a potential therapeutic target and reveal an unexplored mechanism for targeting NuRD-associated cancer dependencies.
    Mesh-Begriff(e) Humans ; Mi-2 Nucleosome Remodeling and Deacetylase Complex/genetics ; Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism ; Histone Deacetylase 1/genetics ; Histone Deacetylase 1/metabolism ; Multiple Myeloma/genetics ; Gene Expression Regulation ; Nucleosomes ; Neuroblastoma/genetics ; Histone Deacetylase 2/genetics ; Histone Deacetylase 2/metabolism
    Chemische Substanzen Mi-2 Nucleosome Remodeling and Deacetylase Complex (EC 3.5.1.98) ; Histone Deacetylase 1 (EC 3.5.1.98) ; Nucleosomes ; HDAC1 protein, human (EC 3.5.1.98) ; HDAC2 protein, human (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98)
    Sprache Englisch
    Erscheinungsdatum 2023-07-24
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-023-01041-4
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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