RESEARCH HIGHLIGHTS
M E TA S TA S I S
there is no single answer to the question of how metastases spread
La ra Cr ow
The evolutionary paths to metastasis that are taken by tumour cells are many. It is often assumed that one disseminated tumour cell initiates metastatic outgrowth (monoclonal seeding), and there is debate about whether primary tumours spread in a linear manner from primary tumour to metastasis to another metastasis and so on, or whether metastases derive from multiple branched spreading events involving disseminated cells from the primary tumour as well as metastases. To try to address this in patients, Gundem et al. investigated the subclonal architecture of primary tumours and metastases from patients with prostate cancer. Gundem et al. carried out whole-genome sequencing of 51 tumours from 10 patients with metastatic prostate cancer. Analyses of the genetic alterations in each of the tumours from each patient allowed the authors to ascertain phylogenetic relationships between tumours in the same patient. In five patients they found that metastases from different organ sites in the same patient had subclonal alterations that must have originated from multiple distinct clones. As some of these clones were also found in the primary tumours, this polyclonal seeding must derive both from the primary tumour and from other metastases. This indicates that polyclonal seeding, rather than the outgrowth of one disseminated clone, may be a common occurrence in prostate cancer metastasis.
/N PG
Spreading the seed
Of the seven patients from whom the primary tumour was also sequenced (including the five patients exhibiting polyclonal seeding), the authors showed that the metastases were more closely related to each other than to the primary tumour. The authors generated ‘body maps’ that illustrate the emergence and seeding of clones between the primary tumour and metastases. One prostate cancer (in one patient) showed both linear and branched metastatic seeding such that some subclones were present in all metastases, whereas other subclones exhibit metastasis–metastasis seeding. Conversely, another prostate cancer showed only linear spread, and different again was another prostate cancer that showed linear spread as well as polyclonal branched seeding between multiple metastases. Eight of the 10 prostate cancers showed metastasis–metastasis spread, although the possibility remains that undetected subclones from the primary tumours are the origin. The authors also identified clones from four prostate cancers that were present as subclones in the primary tumours but were clonal in all of the metastases. These clones constituted less than 50% of the primary tumour samples, and
NATURE REVIEWS | CANCER
in three of these prostate cancers more than one primary tumour subclone seeded metastases. Mapping the genetic alterations revealed that several tumour suppressor genes were inactivated early in tumour evolution and that truncal alterations were common to all clones in the metastases from the same patient. Interestingly, androgen receptor (AR) and AR pathway gene alterations, which are associated with resistance to androgen deprivation therapy (the standard-of-care for metastatic prostate cancer), often occurred after metastasis. Indeed, only 1 of 17 AR amplifications detected in the entire cohort of sequenced tumours and metastases was truncal (that is, occurred early in tumour evolution and was therefore present in the primary tumour and all of the metastases). The evolution of metastasis and metastatic seeding has been a topic of discussion for some time, and these data make it clear that there is no single answer to the question of how metastases spread. It will be intriguing to see whether any common biology can be identified in an effort to target metastatic dissemination. Gemma K. Alderton ORIGINAL RESEARCH PAPER Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature http://dx.doi.org/10.1038/ nature14347 (2015)
VOLUME 15 | MAY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
M E TA S TA S I S
there is no single answer to the question of how metastases spread
La ra Cr ow
The evolutionary paths to metastasis that are taken by tumour cells are many. It is often assumed that one disseminated tumour cell initiates metastatic outgrowth (monoclonal seeding), and there is debate about whether primary tumours spread in a linear manner from primary tumour to metastasis to another metastasis and so on, or whether metastases derive from multiple branched spreading events involving disseminated cells from the primary tumour as well as metastases. To try to address this in patients, Gundem et al. investigated the subclonal architecture of primary tumours and metastases from patients with prostate cancer. Gundem et al. carried out whole-genome sequencing of 51 tumours from 10 patients with metastatic prostate cancer. Analyses of the genetic alterations in each of the tumours from each patient allowed the authors to ascertain phylogenetic relationships between tumours in the same patient. In five patients they found that metastases from different organ sites in the same patient had subclonal alterations that must have originated from multiple distinct clones. As some of these clones were also found in the primary tumours, this polyclonal seeding must derive both from the primary tumour and from other metastases. This indicates that polyclonal seeding, rather than the outgrowth of one disseminated clone, may be a common occurrence in prostate cancer metastasis.
/N PG
Spreading the seed
Of the seven patients from whom the primary tumour was also sequenced (including the five patients exhibiting polyclonal seeding), the authors showed that the metastases were more closely related to each other than to the primary tumour. The authors generated ‘body maps’ that illustrate the emergence and seeding of clones between the primary tumour and metastases. One prostate cancer (in one patient) showed both linear and branched metastatic seeding such that some subclones were present in all metastases, whereas other subclones exhibit metastasis–metastasis seeding. Conversely, another prostate cancer showed only linear spread, and different again was another prostate cancer that showed linear spread as well as polyclonal branched seeding between multiple metastases. Eight of the 10 prostate cancers showed metastasis–metastasis spread, although the possibility remains that undetected subclones from the primary tumours are the origin. The authors also identified clones from four prostate cancers that were present as subclones in the primary tumours but were clonal in all of the metastases. These clones constituted less than 50% of the primary tumour samples, and
NATURE REVIEWS | CANCER
in three of these prostate cancers more than one primary tumour subclone seeded metastases. Mapping the genetic alterations revealed that several tumour suppressor genes were inactivated early in tumour evolution and that truncal alterations were common to all clones in the metastases from the same patient. Interestingly, androgen receptor (AR) and AR pathway gene alterations, which are associated with resistance to androgen deprivation therapy (the standard-of-care for metastatic prostate cancer), often occurred after metastasis. Indeed, only 1 of 17 AR amplifications detected in the entire cohort of sequenced tumours and metastases was truncal (that is, occurred early in tumour evolution and was therefore present in the primary tumour and all of the metastases). The evolution of metastasis and metastatic seeding has been a topic of discussion for some time, and these data make it clear that there is no single answer to the question of how metastases spread. It will be intriguing to see whether any common biology can be identified in an effort to target metastatic dissemination. Gemma K. Alderton ORIGINAL RESEARCH PAPER Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature http://dx.doi.org/10.1038/ nature14347 (2015)
VOLUME 15 | MAY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
