Researchers determine a novel susceptibility to superior prostate most cancers

Researchers from the University of Bern led an international team that identified a novel susceptibility to advanced prostate cancer that no longer responds to hormone therapy. These results could lead to the development of new treatment approaches for men with the most aggressive form of prostate cancer.

Prostate cancer is the third predicted cause of male death in the EU, with 78,800 deaths in 2020 and a death rate of 10 per 100,000 population. While localized prostate cancer is most commonly treated effectively by surgery and radiation therapy, anti-androgen (hormone) therapies are the mainstay of treatment for metastatic prostate cancer. Ultimately, however, resistance to these therapies will develop.

So far, most of the studies of refractory cancers have focused on changes in the DNA sequence in cancer cells – genetic mutations – as the mechanism of resistance to therapy. However, cancers can also become resistant to treatment through radical shifts in cell identity, leading to relapses that may bear little resemblance to tumors in the early stages prior to treatment. This phenomenon, known as ancestral plasticity, is a lesser-known mechanism of tumor progression.

Similar to camouflage, this plasticity allows cancer cells to change appearance and growth machinery to evade therapy. This transformation is seen in a number of treated cancers, including prostate and lung cancers. Prostate cancer is seen to switch to a highly aggressive form of the disease in approximately 10 to 15% of men treated with hormone therapy, and to date there is no standard treatment for these men.

Impersonation in cancer usually occurs when specific genomic mutations are set. Studies previously carried out by Dr. Rubin's group at the University of Bern and the Inselspital of the University Hospital Bern have been published, however, showed that these events are not enough to enable such a transformation. If changes in DNA are not enough, what other changes in cancer cells might enable this transformation? Dr. Rubin's team study focused on "epigenetic" changes. These changes do not involve changes to the genetic DNA code, but rather often regulate gene activity and expression. One type of epigenetic regulators are multiprotein complexes that, depending on their composition, affect the way a cell uses the information contained in its DNA. This in turn determines the cell identity. "Cancer cells can hijack this machinery to encourage their growth against the surrounding normal cells," explains Rubin.

A novel dependency on prostate cancer cells identified

Postdoc in the Rubin Laboratory, Dr. Anke Augspach (postdoc, University of Bern) and Dr. Joanna Cyrta (formerly Weill Cornell Medicine, currently at Institut Curie, France) have nominated dependence on an important epigenetic regulator called the SWI / SNF complex to allow prostate cancer cells to grow.

This addiction can be examined as a susceptibility to the development of new treatments for advanced prostate cancers that are resistant to hormone treatment. "

Dr. Anke Augspach, postdoc, University of Bern

The SWI / SNF complex re-models a cell's DNA to determine which part of the information is accessible to the cell and which part remains silent. Such a regulation can have a wide range of effects on cells, for example on growth or differentiation.

The team of Dr. Rubin showed that certain components of the SWI / SNF complex are highly expressed in the most aggressive types of prostate cancers – those who have experienced an "impersonation". "Since the SWI / SNF complex consists of up to 15 different proteins, this was a technically challenging study," says Rubin. Dr. Rubin's team focused on several key members of the complex and found that several prostate cancer cell lines depend on the SWI / SNF complex for their growth. The results were published today in Nature Communications.

Future work by this team will continue to investigate the mechanisms by which SWI / SNF may be involved in the plasticity process of prostate cancer cells. The development of novel drugs to support patients for whom there are no longer any standard care options is a focus of the Bern Center for Precision Medicine (BCPM) – a joint initiative of the University of Bern and the archipelago.

Source:

Journal reference:

Cyrta, J. et al. (2020) Role of the specialized composition of SWI / SNF complexes in the plasticity of the prostate cancer line. Communication with nature. doi.org/10.1038/s41467-020-19328-1.

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