by Memorial Sloan Kettering Cancer Center

Micrograph showing prostatic acinar adenocarcinoma (the most common
form of prostate cancer) Credit: Wikipedia

The standard treatment for men with advanced prostate cancer is
androgen-deprivation therapy. Androgens are hormones that fuel
prostate cell growth; removing them with either drugs or surgery
causes the prostate gland to shrink by 90%.

Nevertheless, the cells that remain can eventually regrow a tumor, and
when they do, the tumor is usually resistant to further hormone
therapy. It is also more likely to spread to other organs
(metastasize).

A new study from researchers at Memorial Sloan Kettering provides
insight into how the prostate is able to regrow so swiftly. And it is
not what the scientists initially expected.

“Most people, including me, expected to find a rare population of stem
cells that is responsible for regenerating the gland,” says Charles
Sawyers, Chair of the Human Oncology and Pathogenesis Program at MSK
and the corresponding author on the paper, published May 1 in the
journal Science. “But this is not the case.”

Instead, he says, nearly all of the cells that persisted after
hormone-deprivation therapy contributed to the regeneration of the
prostate gland. Most of these were luminal cells, which form the
inside of the hollow organ. The findings have implications for how
doctors think about prostate cancer treatment.

A Cellular Atlas of the Prostate

The investigators made their discovery with the help of a powerful
technique called single-cell RNA sequencing (scRNA seq). This method
of analysis allows scientists to identify which genes are turned on in
many individual cells in a tissue at once. Collaborating with
scientists from the Dana Pe’er lab in the Sloan Kettering Institute
and Aviv Regev’s lab at the Broad Institute, the team performed scRNA
seq on nearly 14,000 cells in the mouse prostate gland. From these
data, they were able to completely map out the cell types found in a
normal mouse prostate.

With the information, they could then determine which cell types
remained in the prostate after the mice received androgen-deprivation
therapy, and which divided to regrow the gland when androgen was
restored.

From these analyses, it was clear that nearly all the luminal cells in
the prostate were dividing, rather than just a subset—as would be
expected if a stem cell population were mainly responsible for
regenerating the gland.

What’s more, the luminal cells (whose typical function is to secrete
fluids) had clearly acquired abilities they don’t usually have in a
hormonally intact animal.

“They became much more stemlike,” says Wouter Karthaus, a senior
postdoctoral fellow in the Sawyers lab and the paper’s first author.
“Without androgens influencing their gene expression, they were free
to turn on other genes and acquire regenerative properties.”

In addition to the mouse work, the investigators performed scRNA seq
on prostate tissue taken from men who had been treated for prostate
cancer. They found a similar pattern of luminal prostate cells that
had acquired the attributes of stem cells. This implies that what is
true of mice may also be true of men.

Plastic Identities

The study’s findings contradict a classic model of how stem cells
regenerate and repair tissue. By that way of thinking, stem cells are
a rare and special type of cell that can give rise to many cell types
yet retain a proliferative capacity. But recent studies—including,
now, this one—have questioned how broadly this model applies across
different organs. At least in the prostate, fully differentiated cells
can become stem cells under the right conditions, this study suggests.

Prior work from the Sawyers lab showed that some prostate cancer cells
possess an ability to change their identity. This is called lineage
plasticity. They can, for example, reprogram themselves to become a
type of prostate cell that does not require androgen to survive.
Lineage plasticity is an important way that prostate cancer cells
eventually develop resistance to hormone-blocking therapies.

What the latest findings mean for treatment is an open question, but
there could be significant implications.

“Androgen-deprivation therapy may be a double-edged sword,” Dr.
Sawyers says. “Lots of cellsdie, but the ones that persist acquire
this stemlike property.”

“It is likely that we push prostate cancer to have a more
progenitor-like state during therapy,” Dr. Karthaus adds.

The team’s next effort will be to identify the molecular and cellular
cues that control this switch in the hope of developing ways to turn
it off.

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Explore further

New, non-hormonal target identified for advanced prostate cancer

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More information: Wouter R. Karthaus et al, Regenerative potential of
prostate luminal cells revealed by single-cell analysis, Science
(2020). DOI: 10.1126/science.aay0267
Journal information: Science

Provided by Memorial Sloan Kettering Cancer Center