Dual-targeting exosomes for improved drug delivery in breast cancer.

Aims: The authors investigated whether displaying more than one homing peptide enhanced the tumor-targeting efficiency of exosomes. Materials & methods: Exosomes from human embryonic kidney cells (HEK293F) were engineered to display either mono- or dual-tumor-penetrating peptides, iRGD and tLyp1. Exosomes were purified via tangential flow filtration followed by ultracentrifugation. Results: When loaded with doxorubicin (Dox), the dual iRGD-tLyp1 exosomes strongly enhanced Dox uptake in both MCF-7 and MDA-MB-231 breast cancer cell lines, superior to single iRGD or tLyp1 exosomes. The dual iRGD-tLyp1 exosomal Dox was also the most potent, with IC50/GI50 values being 3.7-17.0-times lower than those of free Dox and other exosomal Dox. Conclusion: Selecting appropriate combinatorial homing peptides could be an approach for future precision nanomedicine.

Deficiency in mammalian STN1 promotes colon cancer development via inhibiting DNA repair.

Despite the high lethality of colorectal cancers (CRCs), only a limited number of genetic risk factors are identified. The mammalian ssDNA-binding protein complex CTC1-STN1-TEN1 protects genome stability, yet its role in tumorigenesis is unknown. Here, we show that attenuated CTC1/STN1 expression is common in CRCs. We generated an inducible STN1 knockout mouse model and found that STN1 deficiency in young adult mice increased CRC incidence, tumor size, and tumor load. CRC tumors exhibited enhanced proliferation, reduced apoptosis, and elevated DNA damage and replication stress. We found that STN1 deficiency down-regulated multiple DNA glycosylases, resulting in defective base excision repair (BER) and accumulation of oxidative damage. Collectively, this study identifies STN1 deficiency as a risk factor for CRC and implicates the previously unknown STN1-BER axis in protecting colon tissues from oxidative damage, therefore providing insights into the CRC tumor-suppressing mechanism.

Genetic landscape and personalized tracking of tumor mutations in Vietnamese women with breast cancer.

Breast cancer is the leading cause of cancer death in Vietnamese women, but its mutational landscape and actionable alterations for targeted therapies remain unknown. After treatment, a sensitive biomarker to complement conventional imaging to monitor patients is also lacking. In this prospective multi-center study, 134 early-stage breast cancer patients eligible for curative-intent surgery were recruited. Genomic DNA from tumor tissues and paired white blood cells were sequenced to profile all tumor-derived mutations in 95 cancer-associated genes. Our bioinformatic algorithm was then utilized to identify top mutations for individual patients. Serial plasma samples were collected before surgery and at scheduled visits after surgery. Personalized assay tracking the selected mutations were performed to detect circulating tumor DNA (ctDNA) in the plasma. We found that the mutational landscape of the Vietnamese was largely similar to other Asian cohorts, showing higher TP53 mutation frequency than in Caucasians. Alterations in PIK3CA and PI3K signaling were dominant, particularly in our triple-negative subgroup. Using top-ranked mutations, we detected ctDNA in pre-operative plasma in 24.6-43.5% of the hormone-receptor-positive groups and 76.9-80.8% of the hormone-receptor-negative groups. The detection rate was associated with breast cancer subtypes and clinicopathological features that increased the risk of relapse. Interim analysis after a 15-month follow-up revealed post-operative detection of ctDNA in all three patients that had recurrence, with a lead time of 7-13 months ahead of clinical diagnosis. Our personalized assay is streamlined and affordable with promising clinical utility in residual cancer surveillance. We also generated the first somatic variant dataset for Vietnamese breast cancer women that could lay the foundation for precision cancer medicine in Vietnam.