The multifaceted face of prostate cancer
Jeroen Kneppers defended his thesis at the Department of Biomedical Engineering on March 23rd.
Prostate cancer is the most common of all cancers in men worldwide. Although most tumors grow very slowly, the challenge remains in predicting which patients are at risk for progressive disease and developing lethal metastases. The key to this challenge lies in the heterogeneity of prostate cancer, PhD student Jeroen Kneppers discovered during his research. Therefore, the fact that prostate cancer tumors are highly diverse in many ways makes tailor-made therapy all the more important.
Because tumors in prostate cancer usually grow very slowly, waiting is initially sufficient.
That said, predicting which patients are at risk for progressive disease and developing lethal metastases remains a challenge. Kneppers discovered that at the heart of this challenge lies the heterogeneity of prostate cancer; the concept that prostate cancer tumors are highly diverse in many ways.
Different tissue and cellular contexts combine to form the tumor microenvironment, in the presence of multiple genetically distinct tumor lesions but also in variations in molecular regulation.
The growth of prostate cancer is molecularly determined by androgen receptor (AR) signaling. This signaling depends on binding of androgens, such as testosterone, for activation, dimerization and translocation to the nucleus. There, it turns on transcription by binding to elements on the DNA (enhancers) that interact with gene promoters, which then increases gene expression.
The repertoire of AR interactions of these enhancers depends on tissue and cellular contexts to form a spectrum of phenotypes. Moreover, AR interaction landscapes also vary by disease stage, with specific enhancers being activated by AR at different times during disease progression.
Tailored therapy
In his thesis, Kneppers studied and described the role of tumor multifocality, tumor microenvironment and epigenetic heterogeneity of enhancer use of AR in the development and progression of prostate cancer. To better understand the sources and consequences of such phenotypic heterogeneity, he used next generation sequencing on prostate tissue biopsies from patients, (modified) prostate cancer cell lines, genomics, computational simulations and a literature review.
Finding the origin of a prostate cancer metastasis using sequencing on matched primary lesions and lymph node metastases, turned out to fail in 23% of cases. This is relevant because new therapies are targeting organ-sparing treatment methods that, for example, treat only dominant tumors (index lesions) and therefore risk under-treating the patient.
Kneppers then computationally demonstrates that macrophages play an important immunomodulatory role in the microenvironment of prostate cancer tumors and experimentally showed that prostate cancer cells can also develop resistance to tumor cell-killing marcrophages. Finally, using tissues from 88 primary prostate cancer patients, he identified immense heterogeneity in AR binding sites, with only 5% of the sites occurring in half of the patients. Moreover, rare AR binding sites affect gene expression and biochemical progression, making them clinically relevant.
Kneppers concludes: “this study advances the understanding of epigenetic heterogeneity in the context of prostate cancer and describes the discovery that rare and normally overlooked heterogeneous AR binding sites make meaningful contributions to the clinical phenotype. The results of this work further underscore the personalized nature of epigenetics and therefore suggest that patients could benefit from more tailored therapy.”
Title of PhD thesis: Understanding the divergence of prostate cancer genomics among patients: the multi-faceted face of prostate cancer
Supervisors: Wilbert Zwart en Andries Bergman (KNI)