CCBIO seminar: Olivier De Wever
Communication in the tumor environment: diagnostic and therapeutic opportunities
Olivier De Wever
Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Belgium
Communication between cancer cells and their stroma is an essential hallmark for metastasis and therapy resistance. In our research group we attempt to understand the communication between cancer-associated fibroblasts (CAFs) and cancer cells as a response to radiotherapy and as a tool for cancer therapeutics.
Pre-operative radiochemotherapy increases life-expectancy for rectal cancer patients. However, when recurrence arises in the irradiated area, patients have a poor prognosis. Cultures of colorectal CAFs were irradiated with therapeutic doses of 1.8Gy. Treatment of colorectal cancer (CRC) cells with secretome of irradiated CAFs increased cell spreading, cell number, lactate release and glucose uptake. mRNA sequencing revealed differential gene expression significantly clustered in genes associated with cell-matrix adhesion and pro-survival signaling. A protein array screening demonstrated higher secretion of a pro-survival factor, by irradiated CAFs. Secretome of irradiated CAFs stimulated AKT survival pathway in CRC cells. An orthotopic CRC mouse model was used for local tumor irradiation. Interestingly, half of saline-treated mice showed haematogenous spread with metastasis in liver or lungs, in contrast to only 7% of the pro-survival antagonist treatment group. The translational relevance of our data is shown by increased phospho-mTOR immunostaining in cancer cells in close contact with CAFs in samples from radiochemotherapy-treated patients. Our data demonstrates a bystander-type phenomenon in which pro-survival factors by irradiated CAFs alter the phenotype of adjacent CRC cells, promoting CRC progression.
Peritoneal metastasis is life-threatening and is the result of an extensive communication between disseminated cancer cells, mesothelial cells and CAFs. CAFs secrete extracellular matrix (ECM) creating a receptive environment for peritoneal implantation. We exploited CAFs to create biomimetic traps to deceive and redirect cancer cells. Microparticles (MP) containing a CAF-derived ECM-surface are designed to compete with natural niches. Adhesion experiments mimicking the environment of the peritoneal cavity show the selective capture of floating cancer cells from different tumor origins by MP[CAF] compared to control MP. Intraperitoneal delivery of MP[CAF] and sequential removal redirects cancer cell adhesion from the surgical wound to the MP[CAF], delays peritoneal metastasis formation and prolongs animal survival. Our experiments suggest the use of a biomimetic trap based on tumor-environment interactions to delay peritoneal metastasis.
Despite an enormous interest in the role of extracellular vesicles (EVs) as communication vehicles in cancer and their use as biomarkers for diagnosis, prognosis, drug response and recurrence, there is no consensus on dependable isolation protocols. Our research group performed a comparative evaluation of 4 EV isolation protocols for their usability, yield and purity, and their impact on downstream omics approaches for biomarker discovery. Our results demonstrate that implementation of high purification techniques is a prerequisite to obtain reliable omics data and identify exosome-specific functions and biomarkers.
Chairperson: Donald Gullberg, CCBIO