Ghent University / Wever O*
Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer (CRC) cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell cycle arrest, and secretion of paracrine mediators including insulin-like growth factor-1 (IGF-1). Subsequently, RT-activated CAF promoted survival of CRC cells as well as a metabolic switch favoring glutamine consumption through IGF-1 receptor (IGF-1R) activation. RT followed by IGF-1R neutralization in orthotopic CRC models reduced the number of mice with organ metastases. Activation of the downstream IGF-1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from RC patients after neoadjuvant chemoRT. Taken together, our data support the notion that paracrine IGF-1/IGF-1R signaling initiated by RT-activated CAF worsen CRC progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.
Tommelein J1, De Vlieghere E2, Verset L3, Melsens E4, Leenders J5, Descamps B6, Debucquoy A7, Vanhove C8, Pauwels P9, Gespach CP10, Vral A11, De Boeck A12, Haustermans K13, de Tullio P5, Ceelen W14, Demetter P15, Boterberg T16, Bracke M17, De Wever O18.
1 Department of Radiation Oncology and Experimental Cancer Research, Ghent University.
2 Dept Radiation Oncology and Experimental Cancer Research, Univerity Ghent.
3 Department of Pathology, Université Libre de Bruxelles.
4 Department of Gastro-Intestinal Surgery, Ghent University.
5 Laboratory of Medicinal Chemistry - CIRM, University of Liege.
6 Department of Electronics and Information Systems - IBiTech - MEDISIP - INFINITY, Ghent University - iMinds Medical IT.
7 Radiation Oncology, University Hospital Gasthuisberg, Leuven Cancer Institute.
8 Institute Biomedical Technology, Ghent University.
9 Pathology, Ghent University.
10 Molecular and clinical oncology of human solid tumors, INSERM U938.
11 Faculty of Medicine, University of Ghent.
12 Oncology, University of Calgary.
13 KU Leuven.
14 Department of Gastro-Intestinal Surgery, Ghent University Hospital.
15 Pathology, Erasme University Hospital.
16 Radiotherapy, Ghent University Hospital.
17 Radiation Oncology and Experimental Cancer Research, Ghent University Hospital.
18 Laboratory of Experimental Cancerology, Gent University firstname.lastname@example.org.