Transcriptomics analysis unveils the complex interplay between diabetes and hypertension in regulating renal cell carcinoma pathway followed by pancreatic metastasis

Renal cell carcinoma (RCC) is often associated with metabolic disorders such as type 2 diabetes mellitus (T2DM) and hypertension. While existing research has established connections between these metabolic conditions and RCC, the underlying mechanisms driving RCC followed by pancreatic metastasis remain incompletely understood. Therefore, our study aimed to investigate the complex interplay between metabolic disorders (type 2 diabetes and hypertension) and malignancies (renal cell carcinoma and pancreatic cancer). To investigate the hidden link, we performed an integrative transcriptomic analysis. The analysis focuses only on T2DM and hypertension to identify a connection with the RCC pathway. Our analysis revealed that 190 significantly upregulated genes, of which MET emerged as a master regulator in RCC, while KRAS was the key regulator in pancreatic cancer. Furthermore, we identified key microRNAs (has-mir-1-3p, has-mir-16-5p, and has-mir-455-3p) and transcription factors (MBD1, TFDP1, and KLF9) regulate these targets. Additionally, we identified and validated CDC42, PTPN11, TGFB3, and MET as potential prognostic or theragnostic biomarkers. MET, KRAS, and PIK3CD emerged as the most promising therapeutic targets against a panel of 28 repurposable inhibitory drugs. The genetic and immune association suggested that CD8 + T cells are the key immune infiltrate significantly associated with poor survival outcomes in RCC and pancreatic cancer patients. Mutational analysis further highlighted the significance of KRAS G12C, G12V, and G12D mutations, which were common between RCC and pancreatic metastasis. Our study provides critical insights into the statistically significant associations between metabolic disorders and malignancies, emphasizing the potential of tailored therapies alongside shared therapies in managing RCC and its progression to pancreatic metastasis.