Programmed Necrosis

Programmed necrosis to eliminate cancer cells resistant to apoptosis

Yingquan Shan, Akandé Rouchidane, Florence Jollivet, Bertrand Mollereau (PI)

Cell death and cell death resistance are the core of cancer therapy. Most cancer treatments, such as chemotherapy or radiation-based therapies, eliminate cancer cells by triggering apoptosis, which is the most well studied form of programmed cell death. These treatments allow relatively successful treatment for several cancers. Nevertheless, in several malignancies including melanoma, glioblastoma, lung and pancreatic cancers, malignant cells often develop resistance to apoptosis leading to the reduction or loss of treatment efficiency, tumor survival and cancer relapse. Furthermore, apoptotic cancer cells drive the proliferation of neighboring cells by secreting a cocktail of mitogenic molecules such as prostaglandins and ATP. There is thus an urgent need for alternative treatments to apoptosis induction for cancer therapy. Potential new therapeutic approaches include the induction of non-apoptotic programmed cell death in cancer cells that are refractory to apoptosis-inducing agents. Among the various ways that a cell can take to die, necrosis has been neglected for many years and only considered as an accidental form of cell death. However, it was recently realized that necrosis is a highly regulated and genetically controlled process. Nowadays, necrosis is defined as a regulated cell death process that eventually results in cell leakage while it is morphologically characterized by cytoplasmic granulation, cellular/organelles swelling and plasma and nuclear membrane rupture (Napoletano et al 2019). Moreover, tt was proposed that triggering alternative types of cell death such as regulated necrosis can be very effective for cancer treatment by engaging a strong anti-tumorigenic immune response . The most studied form of regulated necrosis, necroptosis, has been tested as an alternative to apoptosis to eliminate cancer cells. However, the role necroptosis in cancer cell elimination gave mix results depending on cancer cell types and oncogenes involved, suggesting that unknown molecular actors orchestrate the dying manners of the cancer cells.

We have uncovered that a p53-dependent programmed necrosis takes place physiologically during spermatogenesis in fly and mice in collaboration with the team of Eli Arama (Weizmann Institute Israël) and Benjamin Gibert (CRCL, Lyon France) (Napoletano et al 2017) . This is the first demonstration that a necrotic program is activated in animals for the physiological elimination of supernumerary cells. Interestingly, inhibiting programmed necrosis in male germ cells induces testis hyperplasia. Moreover, our recent results obtained revealed an intriguing finding: blocking the activation of caspases, proteases that are the principal effectors of apoptosis, enhanced programmed necrosis in both fly retina cells and testis. This is important as relapsing cancer cells are often associated with impaired apoptosis due to caspase inhibition suggesting that cells that are refractory apoptosis are perfect candidates to die by necrosis.

We hypothesize that programmed necrosis is a potent inducer of cell death in cells that are resistant to apoptosis. Moreover, this indicates that key effectors of necrosis are likely to be cleaved and inactivated in presence of functional caspases. We propose to study the molecular mechanisms of programmed necrosis. To that extent, we will perform experiments in conditions with functional caspases and apoptosis but also in conditions with inhibited caspases and apoptosis to mimic cancer cells that are refractory to apoptosis. Our general goal is to gain a better understanding of the molecular pathways leading to necrosis and to identify the main effectors of necrosis in order to shed light on new potential targets for alternative therapies in cancer types that present apoptosis-escaping phenotype.

Collaborators:

Gabriel Ichim, CRCL, Lyon, France

Nicolas Aznar, CRCL, Lyon, France

Fundings:

Ligue contre le cancer, Fondation ARC, INCA