Colorectal Cancer Cells–Derived Exosomal <i>PIK3CA</i> Mutation DNA Promotes Tumor Metastasis by Activating Fibroblast and Affecting Tumor Metastatic Microenvironment

Exosomes participate in the formation of the tumor metastatic microenvironment (TME) by delivering tumor-specific substances. However, current studies mostly focus on exosomal RNA and proteins and lack an in-depth exploration of exosomal DNA. It is discovered that PIK3CA^H1047R mutant DNA in colorectal cancer (CRC) cell-derived exosomes can be delivered into recipient fibroblasts, where they are transcribed and translated, ultimately leading to the activation of fibroblasts into cancer-associated fibroblasts (CAFs) through interaction with the endogenous P85 regulatory subunit of the phosphatidylinositol 3-kinase (PI3K) pathway. CAFs have facilitated tumor cell migration in vitro and promote lung metastasis in vivo by secreting elevated levels of IL6. Additionally, the PIK3CA^H1047R mutation is detected in CAFs at both the primary and metastatic sites, suggesting that it may play a role in promoting metastasis by influencing the TME. Moreover, patients with CRC harboring the PIK3CA^H1047R mutation and exhibiting elevated levels of IL6 are significantly more likely to metastasize. These findings suggest that the simultaneous detection of serum-derived exosomal PIK3CA^H1047R mutation and serum IL6 secretion may serve as a promising diagnostic and prognostic tool for CRC and simultaneous targeting of PIK3CA^H1047R mutation and IL6 may serve as a novel approach for the treatment of CRC.