Therapy-Senescent Lymphoma Cells Bear Potentially Detrimental Stem-Cell Characteristics.
Authors: Milanovic Maja , Dörr Jan , Lenze Dido , Hummel Michael , Dörken Bernd , Schmitt Clemens 
Published: October 2019

Abstract 2836

Premature senescence is a stress-inducible terminal cell-cycle arrest, which, like apoptosis, prevents propagation of aberrantly proliferating cells. DNA-damaging chemotherapy induces cellular senescence, particularly in cells where apoptosis is no longer available (e.g. due to Bcl2 over-expression). Since senescent cells remain vital, it is critical to understand their long-term fate and ultimate impact on outcome. Given the potential reversibility of senescence by additional genetic events, assessment of a senescence-associated tumorigenic capability appears to be crucial for the development of safe pro-senescent treatment regimens. Since “stemness” is a property that – either confined to a putative cancer stem cell population or endowed in all neoplastic cells – enables malignant transformation and propagation, we decided to investigate features of stemness in senescent Eμ-myc-transgenic B-cell lymphomas.

Here, we compared expression changes of stem-cell related gene sets in proliferating vs. treatment-induced senescent (TIS) Eμ-myc lymphoma cells. The clonogenicity and proliferation capacity were assessed in cells released from TIS by acute inactivation of downstream senescence gatekeeper proteins, such as Suv39h1, Klf4 or p53.

Our data show that embryonic stem cell-like (ESCL) gene expression signatures, associated with aggressive tumor behavior decrease with TIS induction in Eμ-myc lymphoma cells. However, the adult tissue stem cell (ATSC) gene signature is highly up-regulated, providing the senescent lymphoma cells with an alternative stemness-maintaining prospective. Similar conversion from an ESCL- to an ATSC-governed program is observed in hematopoietic stem cells shifting from an actively proliferating to a quiescent state. TIS cells presented with high expression levels of reprogramming factors (Klf4 and Sox2), which have the potential to initiate ESCL program, and exhibited up-regulation of several transcripts associated with invasive neoplastic features, like Twist1/2, Snai1/2, Cdh2 or Mmp2These findings suggest that senescent cells retain or even increase their initial malignant capacity by promoting a latent stemness program that is kept in check by cellular senescence. Indeed, upon inactivation of the senescence barrier, cells resumed cycling, and showed an increased clonogenic potential compared to matching proliferating lymphoma cells that had not encountered senescence. The relevance of these genetic changes for tumor progression in vivo is currently under investigation.

These results suggest a more complex relation between senescence and stemness than intuitively expected. The intended execution of the senescence response evokes critical changes in other fundamental, cancer-related cellular programs, opening the possibility of arresting neoplastic cells on one side, but simultaneously promoting aggressive cancer features, like self-renewal, invasion and motility that may become harmful upon disruption of the “senescence shield”. This calls for a thorough functional reassessment of the senescent phenotype, before employing senescence as a therapeutic option.

Disclosures:

No relevant conflicts of interest to declare.