Deciphering the functional role of HOXA9 as driver of colorectal cancer metastasis

• Applicant: Dr. Rene-Filip Jackstadt
• Subject Area: Pathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508880740

Colorectal cancer (CRC) represents the third most prevalent cancer type worldwide, and metastasis is the major cause of mortality. The genetic stepwise progression model of CRC has set an important cornerstone to understand malignant progression; however, three decades later, enormous efforts to characterize the metastatic process still have been unsuccessful in developing therapeutic concepts to eventually improve patient outcome. Particularly, the metastatic cascade appears to select for aggressive clones, however independent of acquiring genetic alterations that drive metastasis. This led to the assumption that aberrant epigenetic or transcriptional changes are key to metastasis. Yet, mechanistic understanding of factors driving these epigenetic changes of CRC metastasis have not been feasible due to lack of appropriate models. The goal of this project is to improve our fragmented understanding of CRC metastasis by focusing on epigenetic programs in cancer cells that facilitate the cancer cell to overcome challenges during metastasis. We have recently developed next-generation genetic mouse models that pave the way for ground-breaking opportunities to investigate metastatic progression of CRC. Initial analysis comparing chromatin accessibility by ATAC-seq of primary tumors and paired metastases revealed that indeed metastases are in a distinct epigenetic state compared to primary tumors. Further analysis identified the transcription factor HOXA9 as a potential driver of CRC progression, stemness and the metastatic state. These findings encourage us to decipher the mechanistic as well as functional role and the biomarker capacities of HOXA9 by focusing on the following three key points: (1) With multi-omics of paired unique patient samples and a novel mouse model we will address the molecular features of cells in metastatic states. (2) By gain and loss of function of HOXA9 in mouse and human organoids and genetic mouse models, we will reveal the functional and molecular mechanisms that control metastasis driven by HOXA9 and whether these cells show for example increased plasticity or stemness features. (3) Through analysis of HOXA9 expression in patient cohorts, we will define the capacity of HOXA9 as a prognostic or diagnostic marker for human CRC. These results will generate insights to the mechanisms that drive metastatsis with implications for novel therapeutic strategies.

• DFG Programme: Research Grants