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NCI Patient-Derived Models Repository (PDMR) - An NCI Precision Oncology Initiative Resource
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Last Updated: 10/28/19

PDX models:

  • Confirmed human origin
  • Confirmed by histopathology to match the patient diagnosis or pathology of provided patient material
  • Complete IDEXX human pathogen assessment
  • Successfully regrown from cryopreserved material
  • Validated STR profiles and human DNA content for the entire distribution lot
  • Whole exome sequence and RNASeq data are available

PDX Model Generation

Patient-Derived Xenograft (PDX): A tumor model generated by implantation of fresh human tissue (tumor, enriched CTCs) into immunodeficient mice. The PDMR host mouse model used is NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG).

  • Originator: Original patient material used for model generation
  • Passage 0 (P0): First mouse passage implanted with the original human specimen

The PDMR expands its models primarily by subcutaneous fragment engraftment to maintain as much tumor heterogeneity as possible. Distribution lots are early passage — generally P1-P4. Because of this, variations in histology and in low allele frequency genetic variants can be observed in lineages within a model. These same types of variations can be expected in PDX models expanded by the recipients of distributed fragments from the repository. While PDX models generally demonstrate a high degree of stability, the PDMR has observed some models that continue to evolve; this caveat should be considered by any investigator requesting models for their research aims.

PDX-Specific Quality Control

Models are distributed only after the PDMR has performed multiple QC steps. As a general reminder, the following distributed material contains a mixture of human tumor and mouse stroma: cryopreserved PDX fragments, DNA vials, RNA vials, and fresh-frozen fragment vials. Murine reads are bioinformatically removed from posted WES and RNASeq files in the PDMR database; however, the reference sequence for the host mouse model used (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG)) can be found on the SOP page for reference.

  • Identifiler (STR profile) is performed on a fragment from every PDX to confirm lineage identity.
  • A fragment from every PDX contributing to a distribution lot undergoes histopathology assessment to confirm diagnosis.
    • PDX tumors that lose histological/morphological characteristics (e.g., de-differentiation) are screened with an IHC panel including markers for human content (Ku80 or hMito), CD45, EBV, cytokeratin, and/or vimentin to confirm the presence of human tumor material (aka high-grade tumor) versus human lymphoma or murine tumor out-growth.
    • Additional markers may be used for certain cancer sub-types.
    • Coming Soon: Breast cancer hormone receptor IHC validation
  • A fragment from every PDX contributing to a distribution lot undergoes PCR assessment for human:mouse DNA ratio. Several models have stably low tumor content (20%-30%) relative to mouse stroma.
    • PDX tumors that lose histological/morphological characteristics (e.g., de-differentiation) are screened by PCR to confirm murine tumor out-growth has not occurred.
  • Human pathogen assessment is performed using the hIMPACT panel from IDEXX. The PDMR does not distribute models that are positive for human immunodeficiency virus, Hepatitis B, or Hepatitis C.
  • Prior to distribution, all models must be proven to regrow from a viably cryopreserved fragment. For this QC step, 3-5 fragments are implanted and monitored for 300 days for regrowth since some models can take up to 200-250 days to regrow to 1000 mm3 from a cryo-preserved sample. If the initial set of implants fails to grow, 3-5 additional fragments from a different cryo-lot are implanted and assessed. To date, very few models have failed this QC step, though some models have a higher percentage take-rate from frozen stock than others. Histopathology is also reconfirmed for all PDX regrown from viably cryopreserved fragments.

Limitations and Caveats of PDX Models

  • Many PDX models grow slowly, both when coming out of the freezer as well as between passages. For some models, you should expect initial implants to take as long as 200 days before tumor is of sufficient size for passage. Representative growth curves for each PDX model are available in the PDMR database in the specimen details.
  • Several models have stably low human tumor content (e.g., 20%-30%). The remaining content would be murine stroma. Pathology Reports are available in the PDMR database for quick tumor/stromal content review: https://pdmdb.cancer.gov/pls/apex/f?p=101:54.
  • The PDMR serially passages tumor fragments (not cell slurries) directly from mouse to mouse so that every PDX lineage can be traced back to the patient tumor. Since intra-tumor heterogeneity can be observed in the models, we cannot guarantee which fragment a requestor will receive. For instance, there may be variation in differentiation level of the tumor or for a stomach adenocarcinoma in the signet ring cell content.
  • The provided PDX pathology, WES, RNASeq, and other model characterization information in the database are representative of that model (data provided for 4-6 representative PDXs). Recipients should perform their own analysis and characterization of the PDXs they grow from the distributed material.
  • The PDMR assesses every passage for the presence of xenograft-associated lymphoproliferative disorders (XALDs). We group the following PDX-associated issues into this classification for simplicity: human lymphoma outgrowth, murine tumor outgrowth, murine lymphoma outgrowth, and graft-versus-host disease (GvHD).
  • Due to the nature of fragment passaging, EBV-driven human lymphomas occurring within a PDX model can develop, but not be identified during histopathologic assessment of one fragment. Not all fragments are created equal; some may maintain sufficient lymphoproliferative content to over-grow the PDX material.
    • Use of early-passage PDXs will carry this risk. The PDMR has observed human lymphoma out-growth as late as passage 3 (P3) from fragment implantation and intermittently within sub-lineages of a model; these lineages are not distributed.
    • Outgrowth of a mouse tumor can also be observed during passaging, and in the PDMR’s experience this is seen more often at later passages.