The Cancer SENESCopedia: A delineation of cancer cell senescence

Jochems, Fleur; Thijssen, Bram; Conti, Giulia De; Jansen, Robin; Pogacar, Ziva; Groot, K. de; Wang, Liqin; Schepers, Arnout; Wang, Cun; Jin, Haojie; Beijersbergen, Roderick L.; Oliveira, Rodrigo Leite de; Wessels, Lodewyk; Bernards, René

doi:10.1016/j.celrep.2021.109441

Cited by 96 publications

(86 citation statements)

References 81 publications

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“…Although therapy-induced senescence is generally considered a favorable event for patient prognoses, the persistence of senescent cells has been shown to increase the risk of oncogenic transformation and to impair tissue functions. Interestingly, it has been reported that the elimination of senescent cells prevents or mitigates senescence-related diseases [ 157 , 177 , 193 ]. Strategies to target senescence in cancer have emerged in the pharmacological panorama.…”

Section: Discussionmentioning

confidence: 99%

“…Due to this marked heterogeneity, a common signature to identify SASP-secreting cells is actually lacking. Notwithstanding, a recent study by Jochems et al has proposed a machine learning-based strategy to detect senescence in in vitro cancer cells [ 157 ]. Similarly, Basisty et al have recently provided the first proteome-based database of SASPs [ 13 ].…”

Section: Dual Role Of Senescence In Pdacmentioning

confidence: 99%

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Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Cortesi

Zanoni

Pirini

et al. 2021

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) has one of the most dismal prognoses of all cancers due to its late manifestation and resistance to current therapies. Accumulating evidence has suggested that the malignant behavior of this cancer is mainly influenced by the associated strongly immunosuppressive, desmoplastic microenvironment and by the relatively low mutational burden. PDAC develops and progresses through a multi-step process. Early in tumorigenesis, cancer cells must evade the effects of cellular senescence, which slows proliferation and promotes the immune-mediated elimination of pre-malignant cells. The role of senescence as a tumor suppressor has been well-established; however, recent evidence has revealed novel pro-tumorigenic paracrine functions of senescent cells towards their microenvironment. Understanding the interactions between tumors and their microenvironment is a growing research field, with evidence having been provided that non-tumoral cells composing the tumor microenvironment (TME) influence tumor proliferation, metabolism, cell death, and therapeutic resistance. Simultaneously, cancer cells shape a tumor-supportive and immunosuppressive environment, influencing both non-tumoral neighboring and distant cells. The overall intention of this review is to provide an overview of the interplay that occurs between senescent and non-senescent cell types and to describe how such interplay may have an impact on PDAC progression. Specifically, the effects and the molecular changes occurring in non-cancerous cells during senescence, and how these may contribute to a tumor-permissive microenvironment, will be discussed. Finally, senescence targeting strategies will be briefly introduced, highlighting their potential in the treatment of PDAC.

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Section: Discussionmentioning

confidence: 99%

Section: Dual Role Of Senescence In Pdacmentioning

confidence: 99%

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Cortesi

Zanoni

Pirini

et al. 2021

IJMS

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“…In addition to directly comparing SenMayo to the R-HSA-2559582 senescence/SASP gene set, we also compared it to five additional senescence/SASP gene sets 40–44 in all of the mouse and human models described above. As shown in Table 2, SenMayo consistently outperformed these gene sets (based on normalized enrichment scores [NES] and p-values) both in the ability to identify senescent cells with aging across tissues and species and in demonstrating responses to senescent cell clearance.…”

Section: Resultsmentioning

confidence: 99%

“…Using publicly available RNA-seq data, we demonstrated applicability across tissues and species and also found that SenMayo performed better than six existing senescence/SASP gene panels. 14,40–44 We next applied SenMayo to publicly available bone marrow/bone scRNA-seq data and successfully characterized hematopoietic and mesenchymal cells expressing high levels of senescence/SASP markers at the single cell level, demonstrated co-expression (where feasible) with the key senescence genes, Cdkn2a/p16 Ink4a and Cdkn1a/p21 Cip1 , and analyzed intercellular communication patterns of senescent cells with other cells in their microenvironment. Based on these analyses, we found that senescent hematopoietic and mesenchymal cells communicated with other cells through common pathways, including the Macrophage Migration Inhibitory Factor (MIF) pathway, which has been implicated not only in inflammation but also in immune evasion, an important property of senescent cells.…”

Section: Discussionmentioning

confidence: 99%

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

Saul

Kosinsky

Atkinson

et al. 2021

Preprint

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Although cellular senescence is increasingly recognized as driving multiple age-related co-morbidities through the senescence-associated secretory phenotype (SASP), in vivo senescent cell identification, particularly in bulk or single cell RNA-sequencing (scRNA-seq) data remains challenging. Here, we generated a novel gene set (SenMayo) and first validated its enrichment in bone biopsies from two aged human cohorts. SenMayo also identified senescent cells in aged murine brain tissue, demonstrating applicability across tissues and species. For direct validation, we demonstrated significant reductions in SenMayo in bone following genetic clearance of senescent cells in mice, with similar findings in adipose tissue from humans in a pilot study of pharmacological senescent cell clearance. In direct comparisons, SenMayo outperformed all six existing senescence/SASP gene sets in identifying senescent cells across tissues and in demonstrating responses to senescent cell clearance. We next used SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from publicly available human and murine bone marrow/bone scRNA-seq data and identified monocytic and osteolineage cells, respectively, as showing the highest levels of senescence/SASP genes. Using pseudotime and cellular communication patterns, we found senescent hematopoietic and mesenchymal cells communicated with other cells through common pathways, including the Macrophage Migration Inhibitory Factor (MIF) pathway, which has been implicated not only in inflammation but also in immune evasion, an important property of senescent cells. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Moreover, using this senescence panel, we were able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways associated with these cells, which may be particularly useful for evolving efforts to map senescent cells (e.g., SenNet). In addition, SenMayo represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

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“…In addition, a Cancer SENESCopedia, which describe both transcriptome and susceptibility to senolytic agents, in a large panel of cancer cells rendered senescent by different compounds, has been created. These authors also define a SENCAN classifier for cancer senescence which measures the probability that a sample is senescent based on RNA-seq data [89]. The expression profiles and the classifier are both available at https://ccb.nki.nl/publications/cancer-senescence/ accessed on 28 September 2021.…”

Section: Ngal and The Saspmentioning

confidence: 99%

NGAL as a Potential Target in Tumor Microenvironment

Crescenzi

Leonardi

Pacifico

2021

IJMS

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The signaling network between cancer and stromal cells plays a crucial role in tumor microenvironment. The fate of tumor progression mainly depends on the huge amount of information that these cell populations exchange from the onset of neoplastic transformation. Interfering with such signaling has been producing exciting results in cancer therapy: just think of anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies that, acting as immune checkpoint inhibitors, interrupt the inhibitory signaling exerted by cancer cells on immune cells or the CAR-T technology that fosters the reactivation of anti-tumoral immunity in a restricted group of leukemias and lymphomas. Nevertheless, many types of cancers, in particular solid tumors, are still refractory to these treatments, so the identification of novel molecular targets in tumor secretome would benefit from implementation of current anti-cancer therapeutical strategies. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a secreted protein abundantly expressed in the secretome of various human tumors. It represents a promising target for the multiple roles that are played inside cancer and stromal cells, and also overall in their cross-talk. The review focuses on the different roles of NGAL in tumor microenvironment and in cancer senescence-associated secretory phenotype (SASP), highlighting the most crucial functions that could be eventually targetable in cancer therapy.

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The Cancer SENESCopedia: A delineation of cancer cell senescence

Cited by 96 publications

References 81 publications

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

NGAL as a Potential Target in Tumor Microenvironment

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