Patient-derived xenografts undergo mouse-specific tumor evolution

Abstract

Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of pre-existing minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Importantly, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have important implications for PDX-based modeling of human cancer.

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

“…Additionally, chromosome 20q gain correlated with an enhanced response to the combination of BKM120, a PI3K inhibitor and LDE225, an smoothened, frizzled class receptor inhibitor, in pancreatic cancer PDXs. Moreover, the sensitivity of breast cancer PDXs to LJM716, an erb‐b2 receptor tyrosine kinase 3 inhibitor, was significantly increased by chromosome 1q gain . Other studies confirmed these findings, showing similar changes in the drug response of PDX models .…”

“…Ben‐David et al . showed that the drug sensitivity of PDX models can be increased by serial transplantation . They demonstrated a positive association between drug response and passaging‐related CNAs in multiple cancer types.…”

“…The molecular instability of serially transplanted PDX models has been reported, and researchers have concluded that the discrepancies mainly occur in early passages . Based on phylogenetic analysis results in a PDAC study, early passage PDX tumors are more likely to maintain the genetic features inherited from parental tumors than later passage PDXs .…”

“…Furthermore, Ben‐David et al . showed copy number alterations (CNAs) and variable drug sensitivity in xenograft tumors after serial passaging . Both studies have raised concerns about the fitness of PDX models in cancer studies …”

Cancer research with a human touch

“…Todd Golub, director of the cancer programme at the Broad Institute of Harvard and MIT in Cam bridge, Massachusetts, and his team studied genomic rearrangements called copynumber variations (CNVs) in 543 PDX models repre senting 24 classes of cancer 5 . They found that expansive regions of CNVs constituting more than 5 million bases had been introduced into 60% of the PDXs after 1 passage from the origi nal mouse to its offspring, and 88% of PDXs after 4 passages.…”