What does prostate cancer have in common with chameleons that can change their skin color? These lizards have a remarkable ability to alter their appearance in response to environmental pressure — that is, changes in their circumstances that threaten their survival. They need to eat, so they can either blend in with muted background colors to help them stalk prey. In the same way, they also camouflage themselves to elude predators. They also need to reproduce, so they flash extremely bright colors, a strategy that helps them compete with rivals.

Lineage plasticity

Like many other tumor cancers, prostate cancer (PCa) cells are like chameleons. They have a property called lineage plasticity which is the “ability of cells to transition from one committed developmental pathway to another.”^[i] This property helps explain why there are so many different cell lines of PCa. In addition, it helps us understand why a specific anti-PCa treatment that called androgen deprivation therapy (ADT) initially blocks cancer spread by depriving the tumor of male hormones, but fails. (When ADT is no longer effective, PCa is called castrate-resistant prostate cancer (CRPC).)

How is it that the PCa cells “outsmart” ADT? It’s important to know that molecular messengers called drivers signal the stages of progression through the cell’s life cycle. A normal prostate cell’s development depends on male hormones (androgens) as molecular messengers. These signaling agents bind to, and activate, cell proteins called androgen receptors (ARs) that are expressed in PCa cells as well as healthy prostate cells. AR signaling drives the growth and proliferation of PCa cells. ADT works as chemical castration to shut off the supply of androgens to the AR receptors, thereby switching off their activity and braking the tumor cells’ development cycle.

However, it doesn’t last. According to a 2022 paper by researchers Tang, et al., the tumor cells adapt in ways that allow them to reactive AR signaling, which “… represents the most common driver of CRPC growth, and next-generation AR signaling inhibitors (ARSIs) are now used [as drugs] in combination with ADT as a first-line therapy.”^[ii] Adding these drugs boosts the effectiveness of ADT, but this serves to increase environmental pressure on the tumor cells. Here’s where lineage plasticity comes in.

In a chameleon-like act of wizardry, the prostate tumor transforms from adenocarcinoma to a neuorendocrine tumor that no longer depends on AR signaling (AR-independent or AR-null): The transition from AR dependence frequently accompanies a change in phenotype resembling developmental transdifferentiation or “lineage plasticity.” Neuroendocrine prostate cancer, which lacks a defined pathologic classification, is the most studied type of lineage plasticity.

However, most AR-null tumors do not exhibit neuroendocrine features and are classified as “double-negative prostate cancer,” the drivers of which are poorly defined.^[iii]

Identifying a new tumor type

It was the conviction of the research team that identifying transcription factors which drive PCa plasticity would offer a direction for developing new therapies to target those drivers. To that end, they developed a pool of heterogeneous genomic cell matter from 40 different tumor samples. “The researchers analyzed these cells’ DNA, RNA, and how compactly their DNA was packaged, a characteristic known as chromatin accessibility. Changes in this packaging contribute to cancer by altering genes’ availability for expression.”^[iv]

From this, they identified four subtypes of CRPC, as well as their dominant transcription factors, or molecular drivers. Two of these subtypes had not been previously recognized. A deeper analysis of subgroup Type 4 pointed to two specific plasticity-activating factors. The authors ultimately propose that developing a therapy aimed at inhibiting these two factors might be used to treat patients with this type of CRPC. This discovery offers hope for future patients when their androgen-dependent PCa mimics the property of a chameleon to transform itself into an AR-null tumor that eludes treatment.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Quintanal-Villalonga, Á., Chan, J.M., Yu, H.A. et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat Rev Clin Oncol 17, 360–371 (2020).
[ii] Tang F, Xu D, Wang S, Wong CK et al. Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets. Science, 2022; 376 (6596).
[iii] Ibid.
[iv] Weill Cornell Medicine. “New cancer subtype may illuminate treatment strategy.” ScienceDaily. ScienceDaily, 27 May 2022.