Unraveling the Role of Microenvironmental Chemokines in Beta-Catenin/TCF Signaling and Gene Occupancy during Colorectal Cancer Metastasis to the Liver and Lung

Dr. Jonathan Rennhack is a senior postdoctoral fellow in the lab of Dr. William Hahn at Dana- Farber Cancer and the Broad Institutes pursuing an independent position with the long-term goal to lead a basic and translational research laboratory geared towards understanding epigenetic and genetic drivers of tumor metastasis. Dr. Rennhack proposes to leverage molecular techniques, patient derived organoids, and mouse models of metastatic dissemination to define critical molecular pathways in metastatic survival of colorectal cancer. This work will also define the microenvironmental signals that cause necessary molecular changes which promote metastatic survival. Due to the significant contribution that metastasis has in the mortality of CRC patients, this is in line with the NCI’s goal to help cancer patients live longer. Dr. Rennhack analyzed genomic, transcriptomic, and enhancer profiles of primary and metastatic colorectal cancer specimens and found liver-derived CCL2 directly promotes the survival of metastatic liver lesions by increasing the expression of the β-catenin partner protein, TCF7. He has shown this network to be critical for continued growth and survival of the metastatic lesion in the liver. However, it remains unknown if the CCL2/TCF7 signaling node is necessary for other sites of metastatic dissemination such as the lung. Preliminary data indicates that other TCF family members are expressed in other sites of metastatic dissemination and could be critical for mediating survival of metastatic lesions in those organs. Based upon this preliminary data it is hypothesized that the metastatic microenvironment influences β-Catenin/TCF complex composition and DNA binding to promote differential gene profiles critical for survival in the lung and liver. This hypothesis will be tested using two interrelated but independent aims. In the first aim the composition and occupancy of the β-Catenin complex during metastatic dissemination to the lung will be defined and functionalized. In the second aim microenvironmental regulators of the β-catenin complex, and subsequently survival within the metastatic microenvironment will be defined and functionally tested. In addition to the scientific directives outlined above, Dr. Rennhack will receive additional training in laboratory management, mentorship, grantsmanship, bioinformatics, and translational science throughout the K22 award. Together the experiments proposed, and the additional training provided in this award will ensure Dr. Rennhack’s success as he transitions to an independent research position and will ensure he obtains additional research funds within the first two years of this award.