Estrogen Receptor β and Dormancy in Hepatic Disseminated Colorectal Cancer Cells

• Applicant: Dr. Georg Flügen
• Subject Area: General and Visceral Surgery
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422215274

The liver is by far the most common site of distant metastasis in colorectal cancer (CRC). Following conventional therapy, roughly 50% of patients suffering from initially localized CRC will develop colorectal liver metastasis (CLM) in time; the risk is higher for men. Even in very early-stage (UICC Stage I) and following complete (R0) resection, ca. 6% of patients will suffer from CLM within 10 years of diagnosis. Following recurrence free survival of 5 years, roughly 2,5% of patients will never-the less develop late CLM, at times 10 years after initial treatment. This long latency until CLM occurs indicates the presence of a pool of disseminated, inactive, clinically not overt tumor cells in the liver, which retain their potential for metastatic outgrowth even following adjuvant therapies. It is now believed that these cells have entered a quiescence program called Dormancy, which is not yet studies extensively. The estrogen receptor β (ERβ) is a potential switch for the activation of this program in CRC. ERβ positive colorectal primary tumors showed a better long-term survival. Previous research indicates a lower risk of liver metastasis in patients with ERβ expressing CRC. In-vitro experiments additionally demonstrated a lower proliferation rate, an induction of cell-cycle arrest and the activation of known pro-dormancy signaling through ERβ activation. These results indicate that ERβ positive tumor cells (circulating and disseminated tumor cells (CTC/DTC)) may activate a dormancy program through ERβ signaling. The ERβ may thus be an interesting and potentially easy to manipulate target to keep disseminated cancer cells in a state of dormancy in-vivo. In this proposal, we first want to elucidate the influence of ERβ expression on metastasis chronology (synchronous vs. metachronous) in a cohort of human CRC and CLM. Following this, we will be the first to use the in-vivo CAM-assay (avian chorioallantoic membrane model) to induce and subsequently isolate GFP-marked ERβ expressing CRC cells from the liver (DTC) and the blood (CTC). The applicant has ample experience with both the use of the CAM-assay, as well as the detection and isolation of CTC and DTC. The fact that a clinically validated ERβ agonist (ERB-041) and an experimentally very well-established antagonist (PHTPP) are commercially available will enable the in-vivo manipulation of the ERβ and thus the exploration of the influence on dormancy induction in CRC CTCs and hepatic DTCs. The results from this study may be of use in the potential clinical evaluation of this treatment.

• DFG Programme: Research Grants