Hematopoietic stem cell conditioned media induces excessive mitochondrial fission via Drp-1 to target colorectal cancer

Mitochondria, often referred to as the “powerhouses of the cell,” are particularly crucial in cancer cells due to their high energy demands. Mitochondrial fusion-fission dynamics play a critical role in regulating signaling pathways and metabolic activities in colorectal cancer (CRC) cells. Increased mitochondrial fission drives metabolic reprogramming, enabling CRCs to proliferate, metastasize, and resist chemotherapy. Paradoxically, excessive fission induces mitochondria-mediated apoptosis. Our previous studies have shown that hematopoietic stem cell-derived conditioned media (CM) modulate the apoptosis pathway and mitochondrial bioenergetics of cancer stem cells by altering the cancer microenvironment. In this study, we found that HSCs-CM facilitates excessive fission in colorectal cancer cells by modulating Drp-1 and inducing the mitophagy-mediated apoptosis pathway, leading to the clearance of these cells. Moreover, proteomics data showed that HSCs-CM dysregulated the electron transport chain complexes, with an exceptionally high degree of dysregulation of complexes III and IV. Metabolomics and RNA sequencing revealed the dysregulation of critical proteins involved in mitochondrial bioenergetics and the autophagy pathway in CRCs treated with CM. Taken together, our studies reveal the therapeutic potential of HSC-conditioned media for treating colorectal cancer.