Abstract
CD95 is best known for its ability to induce apoptosis via a well-characterized pathway involving caspase-mediated proteolytic events. However, in apoptosis-resistant cell lines of diverse cancer types stimulation of CD95 primarily has pro-tumorigenic effects that affect many of the hallmarks of cancer. For instance, in colon cancer cells with a mutant KRAS gene CD95 primarily promotes invasion and metastasis. In the current study, we further investigated the context dependency of the consequences of CD95 activation in colon cancer. We used a series of patient-derived three-dimensional colon cancer cultures and studied their response to stimulation with CD95 ligand (CD95L). CD95L had a strong inhibitory effect on the clone-forming capacity of five out of nine cultures. In line with previous work, these cultures all had a wild-type KRAS gene and expressed high levels of CD95. Furthermore, the most sensitive cultures were characterized by microsatellite instability (MSI) and deficient mismatch repair. The reduced clonogenic growth of MSI-type colonospheres resulting from chronic CD95 stimulation was only partly due to apoptosis as many tumor cells survived treatment, yet were unable to regenerate clones. CD95 stimulation caused an irreversible cell cycle arrest, which was associated with cytokine secretion, similar to the senescence-associated secretory phenotype (SASP), and expression of senescence-associated β-galactosidase. In human colon cancer cohorts, CD95 expression was strongly correlated with the recently identified consensus molecular subtype 1 (CMS1), which mainly consists of MSI-high tumors, and with two independent SASP signatures. Mechanistically, CD95-induced senescence was caused by chronic DNA damage via caspase-activated DNAse resulting in p53 activation and p21 expression, with a minor contribution of the SASP. We conclude that induction of senescence is a hitherto unrecognized consequence of high CD95 expression, which appears to be most relevant for CMS1.
Highlights
CD95 is a cell surface receptor with pleiotropic contextdependent functions
We have previously shown that the presence of oncogenic KRAS in colon cancer cells causes a switch in CD95-signaling output from apoptosis to invasion, which is required for metastatic spread and tumor recurrence.[15,20,21]
We found that chronic CD95L exposure suppressed the colony-forming potential of five out of nine of these cultures by more than 50% (Figure 1a)
Summary
CD95 is a cell surface receptor with pleiotropic contextdependent functions. For instance, it is essential for removing self-reactive T cells or activated peripheral T cells during the termination phase of an immune response.[1,2] The role of CD95 in T-cell homeostasis is largely ascribed to its capacity to activate the classical caspase cascade, which leads to programmed cell death.[1]. We describe a novel tumor-suppressive function for CD95 involving chronic activation of the caspase cascade at sub-apoptotic levels, leading to sustained DNA damage and the induction of p53-dependent senescence. This was largely restricted to KRAS wild-type cultures and was strongly associated with deficient mismatch repair (dMMR) in human colon cancer. The results imply that the development of CD95-targeted therapy for the treatment of human colon cancer holds the potential danger of interfering with an intrinsic tumor suppressor mechanism in a specific subset of human colon tumors
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