The study conducted by investigators in the Catapano and Carbone groups at the Institute of Oncology Research (IOR, affiliated to USI Università della Svizzera italiana) in Bellinzona, Switzerland, finds a new way to eliminate cancer stem cells in prostate cancer and enhance treatment efficacy. The new findings suggest a novel pathway for promoting progressive aging and elimination of cancer stem cells (CSCs) in prostate tumours.
Prostate cancer is a leading cause of death in developed countries. After initial response to hormonal therapies, many patients develop highly aggressive, hormone-refractory tumours for which there are currently limited therapeutic options. Investigators at the IOR have uncovered a novel mechanism that promotes expansion of CSCs in prostate cancer by controlling mitochondrial division and showed that blocking this process leads to the progressive loss of CSCs and has a dramatic impact on tumour growth in multiple prostate cancer models.
The study “Epigenetic control of mitochondrial fission enables self-renewal of stem-like tumour cells in human prostate cancer” is published in Cell Metabolism.
CSCs are a small fraction of the total population of cancer cells in a tumour. CSCs have properties similar to normal stem cells, including the ability to reproduce identical cells with the stem cell-like characteristics avoiding differentiation, aging and death. Importantly, these properties allow CSCs to persist after treatment promoting tumour metastasis and relapse. The balance between self-renewal, differentiation and aging determines the progressive expansion or exhaustion of the CSC pool in tumours. The IOR team is working on the premise that aiming at these fundamental processes in CSCs might lead to novel forms of treatment for cancer.
Mitochondria are highly dynamic intracellular organelles that undergo cycles of mitochondrial division (fission) and fusion, in order to adapt their function to a variety of extra- and intra-cellular conditions. Mitochondrial fission, along with clearance of dysfunctional mitochondria, is essential in normal stem cells determining the cell fate through asymmetric segregation of young and functional mitochondria selectively to the stem cell progeny. This process prevents senescence, the aging of stem cells, and allows the continued self-reproduction of “forever young” stem cells.
The investigators at IOR found that BRD4, a protein that regulates activity of genes by binding to chromatin, controls the survival and expansion of prostate CSCs by promoting mitochondrial fission. In prostate CSCs, BRD4 activates the gene encoding mitochondrial fission factor (mff), a key protein required for mitochondrial division. Blocking the function of BRD4 by genetic knockdown or pharmacological inhibitors (BET inhibitors), which prevent BRD4 binding to chromatin, led to impaired mitochondrial fission and progressive aging and loss of prostate CSCs.
Inhibitors of BRD4 and other BET proteins are currently undergoing clinical evaluation for the treatment of cancer. This study provides novel insights into the antitumor efficacy of BET inhibitors and highlights the applicability of therapeutically targeting BRD4, mitochondrial fission and CSCs in prostate cancer.
The study was a collaborative effort between the two IOR teams of Experimental Therapeutics (Dr. Carlo Catapano) and Prostate Cancer Biology (Dr. Giuseppina Carbone), and investigators from the Oncology Therapeutics Development (Prof. Esteban Cvitkovic, Dr. Maria Eugenia Riveiro), a French CRO specialized in early drug development in oncology. The work was funded by grants from the Swiss National Science Foundation (SNSF), Swiss Cancer League (KLS) and the Ticino Foundation for Cancer Research.