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Growth Control, Stemness, Plasticity and Immunogenicity: The Multiple Faces of (Post-)Senescence in Hematologic Malignancies
Clemens A. Schmitt1 and colleagues
1Charité - Universitätsmedizin Berlin, Max-Delbrück-Center for Molecular Medicine, Berlin, and Johannes Kepler University, Linz (Germany and Austria)
Ultimate stress responses that force proliferating cells out of cycle are key barriers to tumor development and pivotal effector mechanisms in response to anticancer therapies. Cellular senescence, in addition to apoptosis, is such terminal cell-cycle exit program, therefore considered and demonstrated to operate as a tumor-suppressive barrier to full-blown transformation in preneoplastic lesions and as an outcome-improving principle evoked by chemotherapeutic agents and targeted therapeutics in manifest malignancies. A largely pro-inflammatory senescence-associated secretory phenotype (SASP) and latent reprogramming into a stem-like condition during senescence (i.e. senescence-associated stemness [SAS]) reflect components of the senescent state switch that may account for detrimental implications of lastingly persistent senescent cells that avoided immune clearance or secondary cell death. While it is becoming an issue of debate to what extent cancer cells that partially executed the apoptotic cascade may recover and re-enter the cell-cycle with molecular features of this experience engraved, it is increasingly acknowledged that the senescent state switch requires a maintenance machinery, which depends on the appropriate expression of a variety of essential genes. In turn, loss or overexpression of those moieties may force senescent cells to resume proliferation, albeit with some of the profound epigenetic alterations that were acquired during senescence to be carried over to a post-senescent, potentially particularly dangerous cancer cell state.
Hence, cellular senescence comes with dynamic features that determine cancer cell fate beyond a robust cell-cycle arrest and SASP. At the meeting, especially lymphoma-based findings on SAS in clinical treatment failure, transdifferentiation to physiologically unknown cell identities, enhanced T-cell-governed immunogenicity due to newly acquired cellular functionalities, as well as the potential role of senolytic drugs will be discussed. Moreover, surprising implications for diagnosis and treatment of the remarkably unifying senescence-associated plasticity in otherwise highly heterogeneous senescence-undergoing AML blasts will be presented.