Metastasis is still the cause of most deaths from cancer, despite major advances in the fields of molecular and genetic characterisation of tumours. Developing an understanding of how metastatic cells arise and go on to form tumours may uncover more information to aid in the development of new treatments. Current thinking is that tumour cells with stem cell like properties may initiate the formation of metastatic tumours.
Lawson et al., (Nature, 2015) have published an elegant study in which they have succeeded in isolating early stage metastatic cells from patient-derived xenograft (PDX) models of triple negative breast cancer. The authors then examined the gene expression profiles of metastatic cell populations.
Normal human breast epithelium were used to establish a 49 gene differentiation signature as a reference against which to analyse gene differentiation in metastatic cells. They examined these differentiation gene signatures in populations of both basal lineage cells, containing stem cells, and luminal lineage cells containing progenitor and mature cells.
PDX models of triple negative breast cancer were used due to the aggressive, metastasis forming nature of the tumours formed in these mice. Metastatic cells were isolated from mouse lung, lymph node, bone marrow, liver, brain and peripheral blood using PDX breast cancer specific cell surface marker genes (human CD298). The authors found that expression of this marker correlated with the tumour burden observed in the animal and so could then investigate the gene expression signatures of low-burden (early-stage metastatic) vs high-burden (advanced-stage metastatic) disease.
They found that in low-burden tissues, the metastatic cells found were different from the main tumours that they were derived from and that the differentiation gene signature in these cells was of a basal, stem-cell nature. This stem cell differentiation gene signature was conserved in low-burden metastatic cells across all animals and models tested. These metastatic cells expressed very high levels of the pluripotency genes OCT4 and SOX2 that are found in embryonic stem cells. The authors also observed that genes involved in cellular processes such as DNA damage response, chromatin modification, differentiation, apoptosis and cell cycle control were differentially expressed in low-burden metastatic cells. When these low-burden cells were transplanted into mammary glands they found that an unusually high amount of tumour formation was observed, suggesting that these early-stage metastatic cells can initiate tumour formation. The authors concluded that primary tumours contain a rare sub-population of stem-like cells and that a higher percentage of these cells within the tumour correlates with a higher metastatic potential.
Higher-burden metastatic cells expressed lower levels of quiescence and dormancy genes compared to the low-burden metastatic cells, but higher levels of cell cycle genes such as MYC and CDK2, suggesting that there is a shift to a more proliferative gene expression signature with an increasing ability to metastasise. By using a CDK inhibitor (Dinaciclib) the authors were able to demonstrate a reduction in the number of animals presenting with metastatic cells.
What relevance does this study have for drug discovery? The identification and isolation of metastatic cells to study their particular characteristics may enable the identification of potential new targets against metastatic disease. The methods used here to assess metastatic cells could also be used in the development of novel compounds and potentially translate into the clinic to assess patient response to new therapies.
Blog written by Sarah Walker