Ghent University Hospita / Olivier De Wever*
Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs 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 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 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.Significance: These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop.
Tommelein J1,2, De Vlieghere E1,2, Verset L3, Melsens E2,4, Leenders J5, Descamps B6, Debucquoy A7, Vanhove C6, Pauwels P8, Gespach CP9, Vral A10, De Boeck A11, Haustermans K7, de Tullio P5, Ceelen W2,4, Demetter P3, Boterberg T1,2, Bracke M1,2, De Wever O12,2.
1 Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium.
2 Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
3 Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
4 Department of Surgery, Ghent University Hospital, Ghent, Belgium.
5 Center for Interdisciplinary Research on Medicines (CIRM), Université de Liège, Liège, Belgium.
6 Department of Electronics and Information System, iMinds-IBiTech-MEDISIP, Ghent University, Ghent, Belgium.
7 Department of Oncology, Experimental Radiotherapy, KU Leuven, University Hospitals Leuven, Leuven, Belgium.
8 Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.
9 Institut National de la Santé et de la Recherche Médicale, INSERM U938, Molecular and Clinical Oncology, Université Paris VI Pierre et Marie Curie, Paris, France.
10 Department of Basic Medical Sciences, Physiology Group, Ghent University, Ghent, Belgium.
11 Arnie Charbonneau Cancer Centre, University of Calgary, Calgary, Alberta, Canada.
12 Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium. firstname.lastname@example.org.