A new study from the IOR reveals how to eradicate cancer stem cells in prostate tumors
Institute of Oncology Research
The Experimental Therapeutics Laboratory, directed by Prof. Carlo Catapano, at the Institute of Oncology Research (IOR, affilitated to USI and member of Bios+) in Bellinzona, in a new study published in the journal Oncogene, investigates the critical mechanisms leading to the expansion of tumor-initiating cells or cancer stem cells (CSCs) in advanced tumors of the prostate and explores novel strategies to eliminate them.
Prostate cancer is one of the most common cancers in men. A major challenge in managing patients with advanced prostate cancer is the presence and persistence of CSCs that drive disease progression, treatment resistance, and metastatic spread. Importantly, CSCs are intrinsically resistant to standard forms of therapy, including hormone-, chemo-, and immuno-therapy.
The IOR study, led by Dr. Gianluca Civenni, reveals that the sigma-1 receptor (S1R), a protein residing at the interface between the endoplasmic reticulum and the mitochondria (a region known as MAM or mitochondria-associated endoplasmic reticulum membrane), plays a crucial role in controlling the fate of CSCs and their ability to expand and form prostate tumors.
Using clinically relevant preclinical models and integrating transcriptomic and proteomic data, the team found that blocking S1R disrupted the tightly coordinated balance between mitochondrial fission and fusion (mitochondrial dynamics) and critical mitochondrial-nuclear signaling essential for the proliferation and survival of prostate CSCs. Specifically, S1R inhibition by genetic or pharmacological tools hindered the ability of prostate CSCs to partition young and aged mitochondria among stem and non-stem daughter cells at cell division, impairing the unrestricted propagation and self-renewal of the CSC progeny and leading to the progressive exhaustion of their tumor-initiating capability.
The study relied on various collaborations with partners at the IOR and IRB and international collaborators at the University of Münster (DE) and the University of Trieste (IT) that provided complementary expertise in drug design, medicinal chemistry, and structural biology.
The study’s findings uncover a fundamental mechanism linking the ER-mitochondria interface and mitochondrial dynamics to the fate of CSCs and disease progression in prostate cancer patients and position the newly discovered S1R-centered axis as an exploitable target for developing innovative CSC-focused anticancer therapies and groundbreaking cancer treatment strategies.
The study: Integrated control of cancer stemness by σ1 receptor in advanced prostate cancer
