Apoptosis-induced nuclear expulsion in tumor cells drives S100a4-mediated metastatic outgrowth through the RAGE pathway

Published in Cancer
Apoptosis-induced nuclear expulsion in tumor cells drives S100a4-mediated metastatic outgrowth through the RAGE pathway
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Metastasis is a complex process that involves the survival and colonization of the fittest tumor cells in distant organs with most fated to cell death. Various forms of cell death exist, each with distinct morphological, molecular, and genetic features. Apoptosis is a process characterized by nuclear condensation and fragmentation, which culminates in the formation of apoptotic bodies containing packaged chromatin and cellular components. Although apoptotic cell death is typically viewed as a favorable therapeutic outcome, tumor cells can exploit it to enhance their metastatic capabilities. In fact, high rates of apoptotic cell death have been linked to poor prognoses in non-small-cell lung cancer, lymphomas, and glioblastoma.

In this study, we report that tumor cells exhibit an altered apoptotic program characterized by nuclear expulsion and citrullinated chromatin which enhances metastatic outgrowth in the lungs in a Padi4-dependent manner. Through single cell tracking, we uncovered that the occurrence of a calcium spike during apoptosis serves as a trigger for the activation of Padi4. This activation subsequently results in the swift de-condensation of chromatin, with a driving force to explode the nucleus and generation of nuclear expulsion products (NEPs).

Through the profiling of proteins attached to the chromatin, we discovered an enrichment in RAGE pathway proteins, such as S100a4 in mouse NEPs and HMGB proteins in human NEPs respectively. we were able to demonstrate that the production of NEPs by dying cells facilitates proliferation of nearby tumor cells via activation of the RAGE pathway. These observations were reinforced by a wealth of investigations utilizing a mouse model of lung metastasis, where we observed that interrupting apoptosis, nuclear expulsion, and the RAGE pathway impeded metastatic outgrowth.

we extended their investigations to other cancer types and discovered that nuclear expulsion occurred in bladder and lung cancers beyond breast cancer in both mouse and human. To assess the impact of NEPs on cancer patients, we sought to pinpoint a biomarker in patient samples and evaluated if NEPs correlated with a negative prognosis. Their proteomics data identified HMGB3 as a potential biomarker for NEPs when colocalized with citrullinated histone H3. Upon profiling biopsies of patient tumors, we discovered that NEPs were present in approximately 3-10% of breast, bladder, and lung cancer patients, suggesting that this phenotype is not limited to a specific cancer type and has far-reaching implications.

we derived an mRNA-seq to obtain a nuclear expulsion signature from incubating tumor cells with NEPs and discovered that patients whose tumors possessed this signature had a worse prognosis than those who did not. These discoveries prompt a myriad of inquiries that demand further exploration. As nuclear expulsion has been observed in other cell types, such as neutrophils, resulting in the formation of neutrophil extracellular traps (NETs), it is feasible that other non-immune cells may undergo a comparable phenotype. While both NEPs and NETs can be induced by Padi4 citrullination of histones, there are notable disparities in their end products. Notably, NEPs tend to have damage-associated molecular patterns (DAMPs) attached, such as HMGB and S100 proteins, whereas NETs possess enzymes such as neutrophil elastase and myeloperoxidase. Given that HMGB and S100 proteins are among the few proteins known to bind chromatin but also have a function in the extracellular space to activate receptors, it is conceivable that NEPs may impact normal physiology during times of cellular stress and death.

In a clinical context, numerous studies have demonstrated that chemotherapy can heighten the likelihood of metastasis. Since most chemotherapies elicit cell death through apoptosis, it is conceivable that these treatments may trigger significant NEP production, which could have various effects on treatment efficacy, relapse, and distant metastasis-free survival. It would be additional interesting point seeing the effect of NEP production in immune system during massive cell death caused by multiple therapies such as chemotherapy because current study only focused on local effect of NEPs. Therefore, it is crucial to explore the role of NEPs in chemotherapy-induced metastasis and determine whether targeting NEPs could improve treatment outcomes and patient prognosis.

In conclusion, our findings reveal a novel mechanism by which tumor cells can enhance their metastatic capabilities through an altered apoptotic program characterized by nuclear expulsion and citrullinated chromatin. This process results in the production of NEPs that stimulate nearby tumor cell proliferation via the activation of the RAGE pathway. Our observations suggest that NEPs could serve as a potential biomarker for negative prognosis and may impact normal physiology during times of cellular stress and death. Additionally, our results highlight the need to explore the role of NEPs in chemotherapy-induced metastasis and to determine whether targeting NEPs could improve treatment outcomes and patient prognosis. Further investigation into the function and regulation of NEPs may ultimately lead to the development of new therapeutic strategies for cancer patients.

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