EURURO Vol. 72 No. 4

Letter to the Editor

Re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg,

et al. Subgroups of Castration-resistant Prostate Cancer

Bone Metastases Defined Through an Inverse

Relationship Between Androgen Receptor Activity and

Immune Response. Eur Urol 2017;71:776–87

We congratulate Ylitalo and colleagues

[1]

on their

important research article. The authors describe for the

first time two subgroups for castration-resistant prostate

cancer (CRPC) bone metastases: (1) high androgen receptor

(AR) activity and low cellular immune responses; and (2)

low AR activity and high cellular immune responses.

Furthermore, these subgroups seem to be interconnected

via a general metabolic rewiring, indicating that CRPC bone

metastases with high AR activity rely on a different

metabolic phenotype compared to metastases with low

AR activity. The findings presented are certainly of high

clinical importance; however, the study is descriptive,

without further characterization of the mechanistic inter-

play between metabolic phenotype and immune reactivity.

From a methodological point of view, the findings are

based on transcriptomic profiling (whole-genome expres-

sion profiling) and identify cholesterol biosynthesis, methi-

onine degradation, and fatty acid

-oxidation as the

pathways with the greatest upregulation in AR-driven

CRPC. Importantly, key metabolites of these upregulated

pathways, including sarcosine, palmitate, cholesterol,

and

-aminoisobutyrate, have previously been identified

using untargeted metabolomics in a similar patient

cohort

[2] .

Mechanistic investigations of sarcosine showed

that knockdown of glycine-

-methyl transferase, the

enzyme that generates sarcosine from glycine, attenuates

prostate cancer (PC) invasion. Furthermore, it has been

shown that AR expression directly regulates sarcosine

levels, proving the importance of sarcosine as a biomarker

in PC progression or as a therapeutic target

[2]

Summarizing, the earlier metabolomics approach iden-

tified sarcosine as a key metabolite, supporting the authors’

transcriptomic data identifying methionine degradation as

one of the pathways with the greatest upregulation in CRPC.

Both approaches highlight that untargeted transcriptomic

and metabolomic profiling are complementary, thereby

representing enormous target identification potential.

Nevertheless, biological validation is of utmost importance,

as shown for sarcosine, although it is often neglected in

the translational research process, including the present

study

[3]

However, the authors do not discuss how cholesterol

biosynthesis (the pathway with the greatest upregulation)

contributes to the AR responsiveness in CRPC, which could

be of major therapeutic relevance. Recently, Alfaqui and

colleagues

[4]

reported the first

in vitro

data showing that

CYP27A1, an important enzyme involved in regulating

cellular cholesterol homeostasis, is deregulated in PC and

that dysregulation of the CYP27A1/27HC axis contributes

significantly to PC pathogenesis

[4] .

It could be partly shown

that sulfonation of cholesterol regulates AR activity either

through alterations in ligand availability or via interaction

with critical co-regulators

[5]

Therefore, we would like to encourage the authors to

further validate their findings in the patient setting with a

focus on cholesterol biosynthesis and metabolic repro-

gramming in CRPC independent of or dependent on the AR

subgroups. For this, we would like to point out that multi-

omics approaches (transcriptomics, metabolomics, proteo-

mics) as well as stable isotope labeling (eg,

C) could

dissect the CRPC cellular metabolism in high resolution,

because patterns of

C enrichment downstream of a

labeled nutrient provide information about pathway

activity. Ultimately this will allow matching of the right

therapies with the right patients to exploit altered

metabolism and improve CRPC outcomes.

Conflicts of interest:

The authors have nothing to disclose.

References

[1]

Ylitalo EB, Thysell E, Jernberg E, et al. Subgroups of castration- resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response. Eur Urol 2017;71:776–87.

[2]

Sreekumar A, Poisson LM, Rajendiran TM, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 2009;457:910–4.

[3]

Goveia J, Pircher A, Conradi LC, et al. Meta-analysis of clinical metabolic profiling studies in cancer: challenges and opportunities. EMBO Mol Med 2016;8:1134–42. E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) e 1 0 2 – e 1 0 3

available at

www.scienced irect.com

journal homepage:

www.europeanurology.com

DOI of original article:

http://dx.doi.org/10.1016/j.eururo.2016.07.033

http://dx.doi.org/10.1016/j.eururo.2017.05.053

0302-2838/