Conceptually novel cancer therapies - targeting cellular senescence and senescence-associated essentialities in lymphoma Follow-up Proposal "Investigating senescence-associated cancer stemness in clinical treatment failure"

• Applicant: Professor Dr. Clemens A. Schmitt
• Subject Area: Hematology, Oncology
• Term: from 2015 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274248610

Inefficient disease control by systemic therapy is the major reason for death in cancer patients diagnosed with a tumor type or stage no longer treatable by surgical means in curative intent. It’s widely believed that apoptosis-incapable subclones will be selected for in the course of therapy and eventually account for clinical progression and patient death. Especially with respect to conventional chemotherapeutic agents, apoptotic defects are considered the pivotal molecular mechanism underlying treatment failure in the clinic.Our laboratory has a long-standing interest in elucidating molecular control and biological properties of oncogene- or therapy-induced senescence (OIS or TIS, respectively) as a stress-inducible failsafe program in (pre-)neoplastic cells. The senescent terminal proliferative arrest – comparable to apoptosis in this regard – operates as another ultimate cell-cycle exit program. Accordingly, cellular senescence is a tumor-suppressive principle that imposes a barrier to full-blown transformation during cancer formation, or attenuates tumor growth in response to therapy. However, unlike apoptosis, viable senescent cells may persist for extended periods of time, and exert non-cell-autonomous effects due to their massive pro-inflammatory secretion, termed the “senescence-associated secretory phenotype (SASP)”. Whether such chronic secretion has immunogenic, tumor-surveilling or rather mitogenic, thus, tumor-promoting consequences, is an issue of scientific debate. In the previous funding period, we examined cell-autonomous alterations in persistent senescent cells, and identified cell-autonomous epigenetic activation of stem cell pathways, i.e. reprogramming into latent self-renewal capacity or “stemness”, as a potentially detrimental feature of the lasting arrest condition. Senescence-associated stemness (SAS) converted non-stem bulk tumor cells into de novo cancer stem cells, hence, was found to account for particularly aggressive relapses emerging from “post-senescent” cells that – either due to a genetic switch or spontaneously – managed to re-enter the cycle. Since we could link SAS to activated Wnt signaling, genetic or pharmacological Wnt inhibition, in turn, abolished the enhanced tumor aggressiveness exerted otherwise by those post-senescent as compared to the very same individual but never senescent lymphomas. While this discovery was novel and provocative in terms of the remodeling impact senescence has on tumor cell biology, the key question remained, whether treatment failure observed in unbiased models and clinical specimens might be causally related to SAS, not apoptotic insensitivity. In this follow-up project application, we therefore aim at unveiling genetic hints for SAS as a driver of treatment failure and seek to evaluate underlying molecular mechanisms as potential targets of innovative sequential senescent cells-eliminating “senolytic” treatment strategies.

• DFG Programme: Research Grants