Environment exposure to arsenic had been linked to increased incidents of human cancers. In cellular and animal experimental systems, arsenic has been shown to be highly capable of activating several signaling pathways that play critical roles in cell growth regulation, malignant transformation and the stemness of cancer stem-like cells. Emerging evidence indicates certain oncogenic properties of the Nrf2 transcription factor that can be activated by arsenic and many other environmental hazards. In human bronchial epithelial cells, our most recent data suggested that arsenic-activated Nrf2 signaling fosters metabolic reprogramming of the cells through shifting mitochondrial TCA cycle to cytosolic glycolysis, and some of the metabolites in glycolysis shunt the hexosamine biosynthesis and serine-glycine pathways important for the energy metabolism of the cancer cells. In the current report, we further demonstrated direct regulation of oncogenic signals by arsenic-activated Nrf2 and connection of Nrf2 with ATF3 stress transcription factor. Meanwhile, we also highlighted some unanswered questions on the molecular characteristics of the Nrf2 protein, which warrants further collaborative efforts among scientists for understanding the important role of Nrf2 in human cancers either associated or not to environmental arsenic exposure.

Triple-negative breast cancers are highly aggressive with an overall poor prognosis and limited therapeutic options. We had previously investigated the role of mdig, an oncogenic gene induced by some environmental risk factors, on the pathogenesis of breast cancer. However, a comprehensive analysis of the proteomic profile affected by mdig in triple-negative breast cancer has not been determined yet. Using label-free bottom-up quantitative proteomics, we compared wildtype control and mdig knockout MDA-MB-231 cells and identified the proteins and pathways that are significantly altered with mdig deletion. A total of 904 differentially expressed (p < 0.005) proteins were identified in the KO cells. Approximately 30 pathways and networks linked to the pathogenicity of breast cancer were either up- or downregulated, such as EIF2 signaling, the unfolded protein response, and isoleucine degradation I. Ingenuity Pathway Analysis established that the differentially expressed proteins have relevant biological actions in cell growth, motility, and malignancy. These data provide the first insight into protein expression patterns in breast cancer associated with a complete disruption of the mdig gene and yielded substantial information on the key proteins, biological processes, and pathways modulated by mdig that contribute to breast cancer tumorigenicity and invasiveness.

Background/Objectives: Tumor-draining lymph nodes (TDLNs) play a critical role in shaping a pre-metastatic and immunosuppressive niche that facilitates tumor dissemination. However, a robust in vivo model that recapitulates regional lymph node and distant metastasis remains elusive. We sought to establish and characterize an animal model that reliably mimics spontaneous human melanoma progression from primary tumor to regional lymph node and distant organ metastasis. Methods: B16F10-Luc2 melanoma cells were subcutaneously implanted from the hock area into the lower medial thigh of C57BL/6J mice to establish a metastatic melanoma mouse model with reliable regional lymph node metastasis and distant metastasis. Tumor growth was monitored over time. ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and bioluminescence imaging (BLI) were used to track lymph node and lung metastases in vivo. Immunocytochemistry (IHC) was performed to confirm the metastatic melanoma cells in tissues. The immune landscape of metastatic lymph nodes was characterized by Cytometry by Time-Of-Flight (CyTOF). Results: This implantation strategy resulted in consistent primary tumor growth accompanied by reproducible metastasis to ipsilateral inguinal lymph nodes (IILN) and subsequent lung metastasis. Multi-modal imaging (PET/CT and BLI) enabled non-invasive monitoring of metastatic progression in vivo. Histological analyses confirmed melanoma cell infiltration in lymph nodes and lung tissues. Notably, CyTOF profiling revealed a distinct immunological remodeling within the TDLN, characterized by immunosuppressive phenotypes in the tumor-draining ipsilateral inguinal lymph node (IILN) compared with naïve nodes, indicative of a potential immunotolerant environment in tumor-bearing mice associated with metastatic progression. Conclusions: We present a reproducible and clinically relevant syngeneic melanoma mouse model that recapitulates lymphatic dissemination to regional lymph nodes and distant lung metastasis, and mimics the immunosuppressive phenotypes in the tumor-draining lymph node microenvironment seen in human melanoma patients. This model provides a valuable platform for investigating the mechanisms of lymphatic metastasis and the immunological dynamics of TDLNs, with potential applications in evaluating therapeutic strategies targeting metastatic progression.