Prostate Cancer Therapy Resistance: Impact of Stromal Hetero

Prostate cancer (PCa) is a major cause of cancer death among men in western countries and is responsible for more than 90,000 cancer deaths annually in Europe alone. As long as the tumor is organ-restricted, the disease can often be cured by radical prostatectomy or radiation therapy. For advanced stages, after a late diagnosis or a relapse after the first therapy, there are a number of therapy options such as androgen ablation with gonadotropin-releasing hormone (GnRH) analogues or inhibitors, antiandrogens, chemotherapy drugs and radiation therapies are available, but all of them only show a palliative effect. The majority of patients will first develop castration-resistant prostate cancer within 2-3 years and then successively become resistant to the various therapies and medications. Even though the therapeutic options have improved significantly in recent years due to the approval of new drugs for castration-resistant prostate cancer, only a slowdown in the progression but no cure is possible in these stages. The objective of the basic science and translational-oriented research project is to further elucidate the molecular mechanisms underlying the development of resistance in order to further improve the scientific basis for optimal (also individualized) therapy using the currently available therapy options, as well as to establish new therapy targets and therapeutic approaches. We will also characterize the influence of the stromal tumor microenvironment on the development of tumor cell resistance. A better understanding of the molecular mechanisms leading to resistance to therapy is of broad interest for tumor biology research. The knowledge gained herein can potentially provide new ways and strategies for therapeutic interventions and thus improve the quality of life of t he affected patients and ultimately reduce the number of prostate cancer deaths.

Prostate cancer is one of the leading causes of male cancer-related death in Western countries. If detected early, it can often be cured by surgery or radiation. However, once the disease has spread or recurs after treatment, it frequently becomes resistant to therapy. The standard treatment for advanced disease is androgen-deprivation therapy, which blocks male hormones (androgens) that drive and sustain prostate tumor growth. Although patients usually respond at first, most ultimately develop therapy-resistant disease, leaving only limited treatment options. While most therapies focus on killing cancer cells, tumors are complex tissues composed of many different cell types. This project, conducted in collaboration with Prof. Marianna Kruithof-de Julio's group (University of Bern), investigated cancer-associated fibroblasts (CAF). These connective tissue cells surround tumor cells and strongly influence how cancers grow, spread, and respond to treatment. Importantly, CAF are not all the same: some restrain tumor growth, while others promote invasion, suppress immune responses, and contribute to therapy resistance. With the generous support of prostate cancer patients who donated tissue after surgery at the Innsbruck University Hospital for Urology, we established a unique biobank of more than 400 fibroblast cell lines from around 100 individuals. This resource enabled us to identify three distinct CAF types. Crucially, these subtypes were linked to disease severity. An "early-activated" subtype was more common in pre-cancerous lesions and low-grade tumors and was associated with more favorable disease features. These cells expressed the androgen receptor, remained sensitive to androgen-targeted therapies, and depended on androgens for growth. In contrast, a more advanced subtype was enriched in aggressive and high-grade cancers, as well as in therapy-resistant disease. These cells had largely lost the androgen receptor and were insensitive to androgen-deprivation therapy, continuing to grow even when androgens were withdrawn. This finding raises the possibility that androgen-deprivation therapy may inadvertently favor the expansion of this tumor-promoting CAF type and thereby contribute to therapy resistance. We therefore sought to understand what drives androgen receptor loss and maintains the aggressive behavior of these cells. We identified a key signaling network responsible for these changes. Blocking this network in laboratory models reduced the tumor-supporting functions of these fibroblasts, particularly when combined with established anti-androgen drugs. These findings suggest a potential new therapeutic strategy to disrupt the supportive role of CAFs in prostate cancer progression. Overall, our work shows that prostate cancer is not driven by tumor cells alone but by a dynamic cellular ecosystem. Targeting both cancer cells and their supportive microenvironment may improve future treatment strategies. We are indebted to the patients for helping us establish the prostate fibroblast biobank, which provides an important platform for the future development of such combination approaches and for identifying patients at risk of early therapy resistance.