Hauptinhalt

Aktuelle Promotionsprojekte

  • Molecular pathways in the regulation of basement membrane remodelling in tumorigenesis: The role of FRAS1/FREM proteins in prostate cancer progression

    (Assigned medical student: Christina Preuße, 05. 2024)

    Basement membranes (BM) are specialized structures within the extracellular matrix (ECM) that provide essential support to the epithelia, separation and filtration. In addition, they play major roles in regulating cell behaviour, including proliferation, migration, invasion and differentiation. The FRAS1/FREM (Fraser Syndrome Protein 1/FRAS1 Related Extracellular Matrix proteins) family of BM proteins were so far thought to play roles only during the embryonic development, whereas their expression (with the exception of FREM3) was believed to shut down after birth. However, recently it has been suggested that the expression of FRAS1 can be switched back on during certain pathologic conditions, like cancer. Using transcriptomic analyses, we found for the first time the both FRAS1 and FREM2 are highly expressed in aggressive, castration resistant prostate cancer cells. Simultaneously, CRISPR/Cas9-mediated knockout of either FRAS1 or FREM2, results in a dramatic decrease in the prostate cancer cell’s ability to migrate and invade.  Given the importance of FRAS1/FREM in the maintenance of the epithelial BM integrity, in this project we explore how do alterations in the expression levels of FRAS1/FREM affect the progression and severity of prostate cancer. We investigate the role of FRAS1/FREM in the structure and function of the prostate tumor BM as well as the molecular mechanisms behind BM and ECM remodelling that affect the communication between tumor cells with their microenvironment. 

  • The intricate interplay between mutp53 and ferroptosis in metastatic prostate cancer and therapy resistance

    (Assigned medical student: Tamara Borries, 04.2024)

    TP53 is the most critical tumor suppressor and simultaneously the most frequently mutated gene across all cancer types. In contrast to other tumor suppressors that are generally inactivated by deletions or truncations, mutp53 is primarily altered by missense mutations. These changes not only eliminate the normal tumor suppressive p53 function, but also give rise to stable mutant proteins that exhibit novel oncogenic activities (gain-of-function: GOF). The GOF properties of mutp53 drive programs for enhanced invasion, metastasis, and resistance to chemotherapy, thus positioning mutp53 as a significant challenge in the battle against cancer. It is now evident that mutp53 controls various molecular pathways that regulate processes such as: glucose and lipid metabolism, tumor-cell proliferation, ECM remodelling, protein transport and folding, stemness and various types of cells death, like ferroptosis. 

    Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation, which has emerged as a crucial mechanism in cancer biology. Unlike apoptosis or necrosis, ferroptosis is characterized by the accumulation of lethal lipid reactive oxygen species (ROS), leading to membrane damage and cell death. Interestingly, this process is intricately regulated by various metabolic and signalling pathways, including those governing iron metabolism, antioxidant defences and lipid homeostasis. In cancer, ferroptosis may suppress tumor growth by eliminating damaged cells, yet cancer cells often develop mechanisms to evade this, contributing to therapy resistance. Although the function of wt p53 in ferroptosis, via the regulation of the Xc- antioxidant system, is extensively studied, the role of mutp53 remains elusive. Our preliminary data from extensive comparative proteomic analyses between mutp53 expressing prostate cancer cells versus knockout, indicate an involvement of p53 mutants in the regulation of a multitude of ferroptotic molecular cascades, including amino acid, iron and lipid metabolism, antioxidant defence, mitochondrial reactive oxygen species response and peroxisome function. Even more, we found that the ferroptosis-resistance phenotype which is present in mutp53 prostate cancer cells, can be secreted and transferred to the tumor microenvironment, implying a possible functional role in the tumor-cell and tumor-microenvironment communication. In this project we dissect the mutp53-driven molecular pathways underlying these processes and we focus on identifying druggable options for targeting ferroptosis-resistant mutp53 prostate cancer cells and improving therapeutic efficiency. 

  • Mutant p53 and its downstream effector ENTPD5, as druggable molecular ER-stress switches in prostate cancer progression

    (Assigned medical student: Maria Pritsker, 03.2023)

    Prostate cancer (PCa) is one of the most common cancers among men, and a leading cause of death, just behind lung cancer. With over one and half million new cases worldwide and close to four hundred thousand deaths, PCa is a major public health issue, yet highly treatable in its early stages. A significant proportion of men with advanced prostate cancer harbour germline and/or somatic mutations in DNA damage repair genes, including the tumor suppressor TP53. Although a high incidence of p53 mutations is found in both primary and metastatic PCa, the exact role of p53 in this setting remains a puzzle. Intriguingly, recent evidence suggests that p53 mutations are the only indicator individually linked to unfavorable prognosis in PCa, outperforming even genomic androgen receptor alterations. The mechanisms underlying the development and progression of PCa are not limited to tumor cells but also involve the interaction of the tumor with its microenvironment (TME). An altered microenvironment, protects cancer cells from the host immune system and therapeutic interventions, providing conditions for persistence and relapse of the disease after treatment. Thus, deciphering the exact pathways used by tumor cells for reprogramming of the TME, would provide a possibility to develop approaches to block or reverse this process. 

    The enzyme ENTPD5, a UDPase that facilitates the processing of N-glycoproteins in the endoplasmic reticulum (ER), has recently been recognized as a significant player in mutp53’s pro-metastatic signalling. Proper processing in the ER is crucial for the functionality of various proteins, including growth factor receptors and secreted glycoproteins. When misfolded proteins accumulate, it leads to ER stress and activates the unfolded protein response (UPR), which can result in cell death. Tumors often adapt to the increased demands for protein production by developing strategies to evade apoptosis associated with the UPR, thereby enhancing survival. Our research indicates that ENTPD5 is a vital partner of mutp53 in promoting ER-stress resistance in prostate cancer cells, which correlates with increased cell survival and invasiveness as well as therapy resistance. Notably, we found that this phenotype can be transmitted from ER-stress resistant cells to those that are sensitive. We propose that this ER-stress resistance could also be conveyed, potentially in a soluble or vesicle-bound form, to other cell types, such as immune cells or fibroblasts, influencing the tumor microenvironment to favor tumor progression. Given the limited information available regarding the influence of mutp53 on the modulation of the TME, in this project we investigate the effect of clinically relevant “hotspot” p53 mutations on the prostate tumor stroma, with regard to the regulation of ER-stress adaptation. Our goal is to elucidate potentially druggable, non-cell autonomous mechanisms driven by the mutp53/ENTPD5 axis that can be exploited for more efficient therapy management. 

  • Mutp53-driven metabolic reprogramming is a hallmark in mutp53-expressing urological cancers

    (Assigned student: Lena Sachczewski, 03.2024; Assigned clinician scientist: Subhajit Madnal, 01.2023)

    Cancer cells have the astonishing ability to autonomously adjust their metabolic activity across a range of pathways, to satisfy their heightened requirements for energy production, biosynthesis, and the management of oxidative stress. Although metabolic reprograming is mainly regulated by driver mutations, the tumor microenvironement (TME), which can be exhausted of vital nutrients, pushes tumor cells to adapt, via induction of nutrient scavenging mechanisms. Warburg effect, also known as aerobic glycolysis, is the most well-known metabolic trait of cancer cells, presented as a shift from complete oxidation of glucose to incomplete oxidation to lactate even in the presence of oxygen. However, the metabolic alterations in cancer go beyond the Warburg effect, and since this paradoxical process increases the demands of energy by the cells, they then must turn to alternative pathways, like glutamine and fatty acid oxidation. While wild type p53 promotes oxidative phosphorylation instead of glycolysis, metabolic rewiring is a well-established mutp53 function, presented in various cancer types. Briefly, p53 mutants have been shown to: favor glycolysis via upregulation of the glucose transporters GLUT1/4, increase fatty acid biosynthesis (FAS) via binding and inhibiting the energy sensor AMP-activated protein kinase (AMPK), modulate the mevalonate pathway via upregulation of related enzymes, regulate resistance to ferroptosis and cholesterol homeostasis. Since altered metabolism enhances substrate availability for rapidly growing tumor cells, it creates a distinct opportunity for targeted therapies that disrupt the adaptive growth pathways utilized by mutp53. 

    Although systematic testing of p53 GOF mutants has begun to elucidate key molecular mechanisms that drive these processes, yet the role of p53 mutants in metabolic reprograming in prostate and bladder cancers is still unknown. In these projects we focus on: how clinically relevant p53 GOF mutants, regulated the prostate and bladder cancer cell’s metabolism; we investigate how mutp53-driven metabolic adaptation programs can influence the tumor microenvironment to facilitate tumor progression and we explore possible therapeutic vulnerabilities by targeting druggable mutp53 effectors.