Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations

For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab

Table S2 from ASCL1 Drives Tolerance to Osimertinib in <i>EGFR</i> Mutant Lung Cancer in Permissive Cellular Contexts

WES Summary</p

Figure S7 from ASCL1 Drives Tolerance to Osimertinib in <i>EGFR</i> Mutant Lung Cancer in Permissive Cellular Contexts

ASCL1 expression activates an EMT transcriptional program in permissive cellular contexts. Expression of individual EMT marker genes in mutant EGFR lung cancer cell lines and PDXs with or without ASCL1 overexpression.</p

Table S3 from ASCL1 Drives Tolerance to Osimertinib in <i>EGFR</i> Mutant Lung Cancer in Permissive Cellular Contexts

Marker Genes in Clusters from YU-006</p

Figure S8 from ASCL1 Drives Tolerance to Osimertinib in <i>EGFR</i> Mutant Lung Cancer in Permissive Cellular Contexts

Changes in chromatin accessibility in HCC827 and PC9 cells upon ASCL1 expression. Global changes in chromatin accessibility in mutant EGFR lung cancer cell lines following ASCL1 overexpression and osimertinib treatment.</p

Figure S4 from ASCL1 Drives Tolerance to Osimertinib in <i>EGFR</i> Mutant Lung Cancer in Permissive Cellular Contexts

Expression of signature genes in residual disease in PDXs.</p

Table S1 from ASCL1 Drives Tolerance to Osimertinib in <i>EGFR</i> Mutant Lung Cancer in Permissive Cellular Contexts

Patient Information</p

Figure S2 from ASCL1 Drives Tolerance to Osimertinib in <i>EGFR</i> Mutant Lung Cancer in Permissive Cellular Contexts

Drug tolerant residual tumors exhibit variable levels of proliferation and low levels of apoptosis. IHC Quantification and additional IHC results to profile cell proliferation.</p

Figure S5 from ASCL1 Drives Tolerance to Osimertinib in <i>EGFR</i> Mutant Lung Cancer in Permissive Cellular Contexts

Characterization of mutant EGFR lung cancer PDXs at single-cell resolution. Workflow for scRNA-seq on PDXs and single cell data for an additional PDX.</p