Gain Critical Insights from Advanced Cell Models with Real-Time Analysis - 33

Related Article from
linked recurrent genomic changes with prostate cancer spread, identifying causal
drivers of metastatic disease has been held back because of a lack of experimental
models that make it possible to carry out biological and molecular analysis of
metastasis as it occurs, in the context of the whole organism.
To try and provide new insights into the mechanisms of metastatic progression,
Dr. Aytés' team turned to a GEMM of prostate cancer. They found that in their NPK
mouse model pre-metastatic and post-metastatic primary tumor cells demonstrated
very different expression profiles. "...expression profiles from the post-metastatic
primary tumors were very similar to those from lung, liver, and lymph node metastases," they wrote. And by using lineage tracing of primary and metastatic tumor
cells in the animals the researchers were able to identify a molecular signature for
tumor progression in the mouse model. This signature was highly conserved, and
corresponded with a very similar signature of human metastatic prostate cancer
progression that had been previously reported. "... these molecular analyses define
a cell-intrinsic signature of de novo metastasis progression in the NPK mouse model
that is highly conserved with metastasis progression of human prostate cancer."
Subsequent cross-species computational analyses comparing the mouse and human signatures highlighted the histone methyltransferase NSD2 as a conserved
master regulator of metastasis progression. Interestingly, the researchers write,
"NSD2 is a putative cofactor of androgen receptor that has been previously implicated in advanced prostate cancer ..." Subsequent gene expression analyses confirmed that while NSD2 is expressed only in low levels in the non-metastatic prostate
tumors in mice, its expression is elevated in metastatic tumors and their metastases.
Evaluation of data on human prostate cancers and direct examination of primary
and metastatic tumors also found that NSD2 expression increased during cancer
progression at both the mRNA and protein levels, and was much higher in more
advanced compared with earlier stage prostate primary tumors.
Encouragingly, genetically silencing NSD2 in laboratory grown human and mouse
prostate cancer cells led to reduced colony formation and significantly held back
invasion. And genetically inhibiting HSD2 in mouse models of prostate cancer led to
increased survival and reduced metastastic burden, without affecting primary tumor
growth. Similarly, pharmacological inhibition of NSD2 in human prostate cancer xenografts using a compound called MCTP-39 was linked with reduced tumor volume.
"Taken together, these observations demonstrate that increased expression of NSD2
33

| January, 2019

Álvaro Aytés, Ph.D., and
Katia Ruggero, Ph.D.,
from the Bellvitge
Biomedical Research
Institute.

is associated with lethal and metastatic prostate cancer, and establish the functional relevance of NSD2 for metastatic prostate cancer progression," the authors
stated. "Together with the results of silencing NSD2 in vivo, these findings regarding
MCTP-39 treatment suggest that NSD2 may be a target for intervention in advanced
prostate cancer."
The authors say their study demonstrates the value of cross-species evaluation of
molecular data from GEMM and human cancers to identify mechanisms of metastatic progression. "We propose that the general strategy of integrating molecular
analyses of tumors and metastases from relevant GEMMs with cross-species computational analyses of human cancer can be broadly adopted to identify new targets
for prevention, detection, and potentially treatment of metastasis progression for
other cancer types."
The study findings indicate that combining NSD2 inhibitors with inhibition of other
targets, including PI-3 kinase, androgen receptor, the histone methyltransferase
component EZH2, and/or DNA repair mechanisms, "all of which are themselves
targetable and highly relevant for prostate cancer," may offer promising treatments
for metastatic prostate cancer. The researchers also suggested testing out different
n
combinations of therapy in their mouse model.
http://www.genengnews.com
Gain Critical Insights from Advanced Cell Models with Real-Time Analysis

Table of Contents for the Digital Edition of Gain Critical Insights from Advanced Cell Models with Real-Time Analysis
