How cancer cells communicate to their environment under metabolic stress situations

The new work developed in the lab of META-CAN’s coordinator, Cristina Muñoz-Pinedo, has finally seen the light in a paper at PNAS. The study has been possible thanks to an amazing group of researchers and the funding of two MSCA Actions: TRAINERS (GA 675448) and META-CAN (GA 766214).

Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized.

To explore this issue, they analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.

Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells. Franziska Püschel, Francesca Favaro, Jaime Redondo-Pedraza, Estefanía Lucendo, Raffaella Iurlaro, Sandrine Marchetti, Blanca Majem, Eric Eldering, Ernest Nadal, Jean-Ehrland Ricci, Eric Chevet, Cristina Muñoz-Pinedo. PNAS, 2020; DOI: 10.1073/pnas.1913707117. Link.