Prof. Dr. Kruithof-de Julio’s lab focuses on developing and applying tools for precision medicine. Two main areas of interest are Prostate and Bladder cancer.
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-associated death in men (Centers for Disease Control and Prevention, 2014). Although PCa can be effectively treated in its early stages with surgery and androgen deprivation therapy, the cancer becomes castration resistant and refractory to available therapies in a significant fraction of patients. Castration resistance PCa (CRPC) is thought to arise due to pre-existing stem cell-like PCa cells that survive androgen-deprivation therapy (castration) in a dormant state and then re-initiate tumor growth and metastasis. Therefore, it is critical to identify and target signaling pathways that fuel these cells and drive the castration resistant stage of the disease associated with metastasis and poor patient survival.
Bladder cancer is the fifth most common cancer in the Western world. UCB presents either as non-muscle-invasive (NMIBC) or as muscle-invasive carcinoma (MIBC). NMIBC proliferates continuously but rarely progresses or forms metastasis. It, however, frequently recurs within few months (50-70%). Acquisition of p53 or RB1 mutations can lead to genetic instability and progression to MIBC although this happens rarely (15%). On the other hand, MIBC is genetically instable and acquires further mutations that affect cell/cell and cell/stroma interactions. This leads to an invasive phenotype and allows the tumor metastasize, resulting in very low survival rate of < 50%. By combining conditional mouse models, organoid culture (human and mouse), organoid on CHIP, genomics and metabolomics we aim to characterize the molecular pathways that are associated with therapy resistance and develop novel therapeutics that tackle the resistant disease.
We are delighted to announce that PhD Candidate Martina Minoli successfully defended her doctoral dissertation on Wednesday, 11 July 2023 at the University of Bern.
Listen to Dr. Minoli, a brilliant and young scientist, was a great pleasure as she defended with great success her wonderful thesis and great publication on bladder organoids.
We would like to congratulate her warmly and wish her all the best for her future career!
Despite the advances in bone fracture treatment, a significant fraction of fracture patients will develop non-union. Most non-unions are treated with surgery since identifying the molecular causes of these defects is exceptionally challenging. In this study, compared with marrow bone, we generated a transcriptional atlas of human osteoprogenitor cells derived from healing callus and non-union fractures. Detailed comparison among the three conditions revealed a substantial similarity of callus and nonunion at the gene expression level. Nevertheless, when assayed functionally, they showed different osteogenic potential. Utilizing longitudinal transcriptional profiling of the osteoprogenitor cells, we identified FOS as a putative master regulator of non-union fractures. We validated FOS activity by profiling a validation cohort of 31 tissue samples. Our work identified new molecular targets for non-union classification and treatment while providing a valuable resource to better understand human bone healing biology.
Bladder Cancer (BLCa) inter-patient heterogeneity is the primary cause of treatment failure, suggesting that patients could benefit from a more personalized treatment approach. Patient-derived organoids (PDOs) have been successfully used as a functional model for predicting drug response in different cancers. In our study, we establish PDO cultures from different BLCa stages and grades. PDOs preserve the histological and molecular heterogeneity of the parental tumors, including their multiclonal genetic landscapes, and consistently share key genetic alterations, mirroring tumor evolution in longitudinal sampling. Our drug screening pipeline is implemented using PDOs, testing standard-of-care and FDA-approved compounds for other tumors. Integrative analysis of drug response profiles with matched PDO genomic analysis is used to determine enrichment thresholds for candidate markers of therapy response and resistance. Finally, by assessing the clinical history of longitudinally sampled cases, we can determine whether the disease clonal evolution matched with drug response.
