Modulating DNA damage response in uveal melanoma through embryonic stem cell microenvironment.

BACKGROUND: Uveal melanoma (UVM) is the most common primary intraocular tumor in adults, with a median survival of 4-5 months following metastasis. DNA damage response (DDR) upregulation in UVM, which could be linked to its frequent activation of the PI3K/AKT pathway, contributes to its treatment resistance. We have reported that embryonic stem cell microenvironments (ESCMe) can revert cancer cells to less aggressive states through downregulation of the PI3K signaling, showing promise in modulating the DDR of UVM. METHODS: Since nonhomologous end joining (NHEJ) is the main DNA repair mechanism in UVM, this study utilized gene expression analysis and survival prognosis analysis to investigate the role of NHEJ-related genes in UVM based on public databases. Xenograft mouse models were established to assess the therapeutic potential of ESC transplantation and exposure to ESC-conditioned medium (ESC-CM) on key DNA repair pathways in UVM. Quantitative PCR and immunohistochemistry were used to analyze NHEJ pathway-related gene expression in UVM and surrounding normal tissues. Apoptosis in UVM tissues was evaluated using the TUNEL assay. RESULTS: PRKDC, KU70, XRCC5, LIG4 and PARP1 showed significant correlations with UM progression. High expression of PRKDC and XRCC5 predicted poorer overall survival, while low PARP1 and XRCC6 expression predicted better disease-free survival in UVM patients. ESCMe treatment significantly inhibited the NHEJ pathway transcriptionally and translationally and promoted apoptosis in tumor tissues in mice bearing UVM. Furthermore, ESC transplantation enhanced DDR activities in surrounding normal cells, potentially mitigating the side effects of cancer therapy. Notably, direct cell-to-cell contact with ESCs was more effective than their secreted factors in regulating the NHEJ pathway. CONCLUSIONS: Our results suggest that NHEJ-related genes might serve as prognostic markers and therapeutic targets in UVM. These findings support the therapeutic potential of ESC-based therapy in enhancing UVM sensitivity to radiochemotherapy and improving treatment outcomes while minimizing damage to healthy cells.

A Strategy to Design Cu2MoS4@MXene Composite With High Photothermal Conversion Efficiency Based on Electron Transfer Regulatory Effect.

Using photothermal therapy to treat cancer has become an effective method, and the design of photothermal agents determines their performance. However, due to the major radiative recombination of a photogenerated electron in photothermal materials, the photothermal performance is weak which hinders their applications. In order to solve this issue, preventing radiative recombination and accelerating nonradiative recombination, which can generate heat, has been proved as a reasonable way. We demonstrated a Cu2MoS4@MXene nanocomposite with an obviously enhanced photothermal conversion efficiency (η = 87.98%), and this improvement can be attributed to the electron migration. Then, a mechanism is proposed based on the electron transfer regulatory effect and the localized surface plasmon resonance effect, which synergistically promote nonradiative recombination and generate more heat. Overall, our design strategy shows a way to improve the photothermal performance of Cu2MoS4, and this method can be extended to other photothermal agents to let them be more efficient in treating cancer.