Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

Haston, Scott; González-Gualda, Estela; Morsli, Samir; Ge, Jianfeng; Reen, Virinder; Calderwood, Alexander; Moutsopoulos, Ilias; Panousopoulos, Leonidas; Deletic, Polina; Carreno, Gabriela; Guiho, Romain; Manshaei, Saba; González-Meljem, José Mario; Lim, Ho Yeong; Simpson, Daniel J.; Birch, Jodie; Pallikonda, Husayn Ahmed; Chandra, Tamir; Macías, David; Doherty, Gary J.; Rassl, Doris M.; Rintoul, Robert C.; Signore, Massimo; Mohorianu, Irina; Akbar, Arne N.; Gil, Jesús; Muñoz‐Espín, Daniel; Martı́nez-Barberá, Juan Pedro

doi:10.1016/j.ccell.2023.05.004

Cited by 56 publications

(40 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, there are also reports suggesting that targeting senescent cells in adipose tissue 31 or even immune-cell senescence 37 may also play a role. In this regard, recent studies also suggest that the elimination of macrophage populations with senescent features can also improve tissue decline in mice 38,39 . Whether or not these macrophages are truly 'senescent' or have an alternative cell state is a topic of debate; regardless, given that we observe a fraction of uPAR-expressing macrophages that also co-express SA-b-gal and senescence-associated transcriptional signatures accumulating in aged tissues it seems likely that their elimination may contribute to the phenotypes we observe.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Amor,

Fernández-Maestre,

Chowdhury

et al. 2023

Preprint

View full text Add to dashboard Cite

Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline1,2. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness3-7. While small-molecule drugs capable of eliminating senescent cells (known as ‘senolytics’) partially replicate these phenotypes, many have undefined mechanisms of action and all require continuous administration to be effective. As an alternative approach, we have developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and previously showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis8. We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, a single administration of a low dose of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

show abstract

Section: Discussionmentioning

confidence: 99%

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Amor,

Fernández-Maestre,

Chowdhury

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…38 In addition to driving tumorigenesis, KRAS mutations also induce senescence in microenvironment components, including macrophages and endothelial cells. 39 IDH-mutated intrahepatic cholangiocarcinoma exhibits a tumor microenvironment that is characterized by decreased CD8 + T cell-mediated immune activation. 40 Furthermore, the presence of R-2-HG in gliomas inhibits the differentiation and activation of myeloid cells, resulting in immune vulnerabilities caused by immunosuppressive tryptophan catabolism.…”

Section: Discussionmentioning

confidence: 99%

Targeted single‐cell RNA sequencing analysis reveals metabolic reprogramming and the ferroptosis‐resistant state in hematologic malignancies

Shen,

Dong,

Kong

et al. 2023

Cell Biochemistry & Function

View full text Add to dashboard Cite

Hematologic malignancies are the most common hematopoietic diseases and a major public health concern. However, the mechanisms underlying myeloid tumors remain unknown owing to the intricate interplay between mutations and diverse clonal evolution patterns, as evidenced by the analysis of bulk cell‐derived omics data. Several single‐cell omics techniques have been used to characterize the hierarchies and altered immune microenvironments of hematologic malignancies. The comprehensive single‐cell atlas of hematologic malignancies provides novel opportunities for personalized combinatorial targeted treatments, avoiding unwanted chemo‐toxicity. In the present study, we performed transcriptome sequencing by combining single‐cell RNA sequencing (scRNA‐seq) with a targeted oncogenic gene panel for acute myeloid leukemia, overcoming the limitations of scRNA‐seq in detecting oncogenic mutations. The distribution of oncogenic IDH1, IDH2, and KRAS mutations in each cell type was identified in the bone marrow (BM) samples of each patient. Our findings suggest that ferroptosis and metabolic reprogramming are involved in the tumorigenesis and chemotherapy resistance of oncogenic mutation‐carrying cells. Biological progression via IDH1, IDH2, and KRAS mutations arrests hematopoietic maturation. Our study findings provide a rationale for using primary BM cells for personalized treatment in clinical settings.

show abstract

“…It has recently been reported that macrophages can acquire senescence phenotypes and promote early lung tumorigenesis 34,35 . Indeed, we also observed that the majority of C12FDG+ cells upon muscle injury were macrophages (Figure 1C & 1D).…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNAseq reveals the pro-regenerative role of senescent FAPs in muscle regeneration

Chen,

Saclier,

Chantrel

et al. 2023

Preprint

View full text Add to dashboard Cite

Muscle regeneration is associated with transient induction of cellular senescence. However, the role of senescence in muscle regeneration of young mice remains unclear. Using a mouse model deficient in both Cdkn1a and Cdkn2a, we find that a marked reduction in senescent cells correlates with delayed muscle regeneration. Single-cell RNA sequencing reveals a heterogeneous senescence program composing of multiple cell types. Notably, senescent fibro-adipogenic progenitors (FAPs) upregulate Mcl-1 to acquire apoptosis resistance. Moreover, removing senescent FAPs using a Mcl-1 inhibitor S63845 impairs muscle regeneration. Furthermore, we find that senescent FAPs promotes myogenic differentiation in a paracrine manner. Hence, these results highlight the beneficial role of senescent stromal cells in supporting muscle regeneration.

show abstract

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

Cited by 56 publications

References 66 publications

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Targeted single‐cell RNA sequencing analysis reveals metabolic reprogramming and the ferroptosis‐resistant state in hematologic malignancies

Single-cell RNAseq reveals the pro-regenerative role of senescent FAPs in muscle regeneration

Contact Info

Product

Resources

About