Abstract
New strategies are desperately needed for the treatment of metastatic colorectal cancer. Early diagnostic techniques have improved the survival rate for individuals with early stage disease; however, the five-year survival rate for patients with metastatic disease is less than 10%. Understanding the mechanisms responsible for disease progression and metastasis is a critical need for these patients. Human helicase-like transcription factor is a tumor suppressor epigenetically silenced during the progression of colorectal cancer. To examine how exactly does silencing HLTF contribute to tumorigenesis, we developed a cell-line derived xenograft model to compare the extremes of disease development. We compared the initial phase in which cancer cells that express helicase-like transcription factor are located in a tumor microenvironment where helicase-like transcription factor is absent vs the final metastatic phase in which neither the cancer cells nor the cells of the tumor microenvironment express helicase-like transcription factor. Combinatorial use of RNA sequencing technology with species-specific mapping, spatial transcriptomics, immunohistochemistry and mass spectrometry provided a holistic understanding of glutathione-based antioxidant defense in the model. The collective re-evaluation of the data revealed changes in replication independent non-coding RNAs and a histone subtype previously unreported.