Senescence-associated Secretory Phenotype Research Articles

Nicotinamide mononucleotide suppresses cellular senescence and increases aquaporin 5 expression in the submandibular gland of aged male mice to ameliorate aging-related dry mouth.

Dry mouth results from decreased saliva secretion due to aging or drug side effects. Decreased saliva secretion causes dryness in the oral cavity that makes swallowing difficult and increases the risk of aspiration pneumonia. There are few fundamental treatments for dry mouth. Here we investigated whether treatment of old mice with nicotinamide mononucleotide (NMN) improved factors associated with dry mouth. Young (16-week-old) and old (113-week-old) male mice were treated subcutaneously with saline or NMN (300mg/kg) once every two days for four weeks and saliva secretion was measured. The amount of nicotinamide adenine dinucleotide (NAD+) in salivary gland tissues was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene expression in the intestinal tract and salivary glands was measured by real-time PCR. The population of cells with acetylation in the submandibular gland was quantified by immunohistological staining. SA-β-gal activity in the submandibular gland was measured to assess cell senescence. Statistical analysis was performed by one-way analysis of variance with Tukey post hoc analysis. The submandibular glands from old mice treated with NMN exhibited increased saliva secretion and NAD+ levels, which both decrease with aging. In addition, the submandibular glands from NMN-treated old mice had decreased acetylation, numbers of senescent cells, and levels of senescence-associated secretory phenotype (SASP) factors, which all increase with aging, as well as increased aquaporin5 (AQP5) mRNA expression. NMN administration may improve dry mouth by regulating cellular senescence in the submandibular gland and increasing expression of AQP5, a water channel involved in saliva secretion, to inhibit age-related decreases in saliva secretion. It is necessary to elucidate further mechanism and confirm its effectiveness in humans.

TPR is required for cytoplasmic chromatin fragment formation during senescence.

During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme - the senescence associated secretory phenotype (SASP) - driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.

Clusterin Deficiency Promotes Cellular Senescence in Human Astrocytes.

The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.

Aging Lung: Molecular Drivers and Impact on Respiratory Diseases—A Narrative Clinical Review

The aging process significantly impacts lung physiology and is a major risk factor for chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, and non-IPF interstitial lung fibrosis. This narrative clinical review explores the molecular and biochemical hallmarks of aging, such as oxidative stress, telomere attrition, genomic instability, epigenetic modifications, proteostasis loss, and impaired macroautophagy, and their roles in lung senescence. Central to this process are senescent cells, which, through the senescence-associated secretory phenotype (SASP), contribute to chronic inflammation and tissue dysfunction. The review highlights parallels between lung aging and pathophysiological changes in respiratory diseases, emphasizing the role of cellular senescence in disease onset and progression. Despite promising research into modulating aging pathways with interventions like caloric restriction, mTOR inhibitors, and SIRT1 activators, clinical evidence for efficacy in reversing or preventing age-related lung diseases remains limited. Understanding the interplay between aging-related mechanisms and environmental factors, such as smoking and pollution, is critical for developing targeted therapies. This review underscores the need for future studies focusing on therapeutic strategies to mitigate aging’s detrimental effects on lung health and improve outcomes for patients with chronic respiratory conditions.

Tales of Cancer-Induced Bone Disease from the Senescent Osteocyte Crypt

Cancer-induced bone disease greatly diminishes the quality of life for patients with bone metastatic breast cancer, resulting in painful skeletal-related events including bone loss and fracture. Improved understanding of the roles of osteoblasts and osteoclasts, and how tumors alter their biology, has led to blockbuster therapies that significantly reduce skeletal-related events, but the disease remains incurable. However, emerging technologies and tools for studying the role of other stromal and immune components in controlling tumor–host interactions have begun to reveal new insights that may yield tractable therapeutic targets to further mitigate the painful effects of bone metastases. In this issue of Cancer Research, Kaur and colleagues study osteocytes, which are terminally differentiated osteoblasts and entombed within the bone matrix, from established bone metastatic breast cancer and report how the disease ages them as characterized by a senescence-associated secretory phenotype. This premature development of osteocyte senescence in turn enhances bone destruction and osteoclastogenic potential. Targeting senescent cells using senolytics suppressed bone resorption and preserved bone mass. Collectively, these findings underscore osteocyte involvement in the “vicious cycle” of bone metastasis, and targeting senescent osteocytes represents a new avenue for managing cancer-induced bone disease.See related article by Kaur et al., p. 3936

Fifty-hertz magnetic fields induce DNA damage through activating mPTP associated mitochondrial permeability transition in senescent human fetal lung fibroblasts

With the rapid development and using of electromagnetic technology, artificial electromagnetic fields (EMFs) have become an emerging environmental factor in our daily life. Extremely-low-frequency (ELF) magnetic fields (MFs), generally generated by power lines and various electric equipment, is one of the most common EMFs in the environment which were concerned for the potential impact on human health. Base on limited evidence, ELF-MFs have been classified as possible carcinogen to human by International Agency for Research on Cancer (IARC), but the mechanisms have not been fully elucidated. Senescent cells are a group of special cells, characterized by cell cycle arrest, senescence-associated secretory phenotype (SASP), accumulation of macromolecular damage, and metabolic disturbance, play important role in fetal development, tissue aging, and even carcinogenesis. Thus, EMFs may promote carcinogenesis by affecting senescent cells, however, there are few studies. In this study, we found that exposure to 50 Hz MFs at 1.0 mT for 24 h could induce significant DNA damage in senescent but not non-senescent human fetal lung fibroblast suggested that senescent cells are more sensitive to 50 Hz MFs on DNA damage, and further results revealed that reactive oxygen species (ROS) generation mediated by mitochondrial permeability transition pore (mPTP) activation play critical role in this process. Our results indicated that cellular senescence can lead to cell sensitivity to the DNA damage effect of 50 Hz MFs, however, whether this play important role in mediating the carcinogenesis of EMFs await further study.

Andrographolide prevents renal fibrosis via decelerating lipotoxicity-mediated premature senescence of tubular epithelial cells

Excessive lipid accumulation often occurs in the early stage of chronic kidney disease (CKD) which is prone to induce oxidative stress and mitochondrial damage, promoting the progression of kidney fibrosis. Andrographolide (AP), a multifunctional natural terpenoids derived from Andrographis paniculate, has been suggested to play beneficial roles in metabolic disorders-associated disease. Here, we reported that AP effectively counteracts tubule injury and interstitial fibrosis in mice fed with a long-term high-fat diet (HFD). AP treatment decreased HFD-induced lipid accumulation in kidney parenchyma and attenuated lipotoxicity-mediated oxidative stress and mitochondrial dysfunction, resulting in a marked decrease in of tubular cell senescence. Importantly, AP inhibited senescence-associated secretory phenotype (SASP) secretion by senescent tubular cells, and in turn suppressed proliferation and activation of fibroblasts in a paracrine effect. Furthermore, we revealed that AP functions as an AMP-activated protein kinase (AMPK) activator to ameliorate renal lipid accumulation through coordinately modulating AMP-activated protein kinase AMPK target genes. By stimulation of AMPK activity, AP protects injured kidney against tubular cell senescence and fibroblast activation. These results suggest the potential therapeutic application of AP in the prevention and treatment of CKD, highlighting the promising drug strategy of targeting the lipotoxicity-mediated premature senescence in tubular cells.

ROS-Induced Gingival Fibroblast Senescence: Implications in Exacerbating Inflammatory Responses in Periodontal Disease.

Periodontal disease is the pathological outcome of the overwhelming inflammation in periodontal tissue. Cellular senescence has been associated with chronic inflammation in several diseases. However, the role of cellular senescence in the pathogenesis of periodontal disease remained unclear. This study aimed to investigate the role and the mechanism of cellular senescence in periodontal disease. Using single-cell RNA sequencing, we first found the upregulated level of cellular senescence in fibroblasts and endothelial cells from inflamed gingival tissue. Subsequently, human gingival fibroblasts isolated from healthy and inflamed gingival tissues were labeled as H-GFs and I-GFs, respectively. Compared to H-GFs, I-GFs exhibited a distinct cellular senescence phenotype, including an increased proportion of senescence-associated β-galactosidase (SA-β-gal) positive cells, enlarged cell morphology, and significant upregulation of p16INK4A expression. We further observed increased cellular reactive oxygen species (ROS) activity, mitochondrial ROS, and DNA damage of I-GFs. These phenotypes could be reversed by ROS scavenger NAC, which suggested the cause of cellular senescence in I-GFs. The migration and proliferation assay showed the decreased activity of I-GFs while the gene expression of senescence-associated secretory phenotype (SASP) factors such as IL-1β, IL-6, TGF-β, and IL-8 was all significantly increased. Finally, we found that supernatants of I-GF culture induced more neutrophil extracellular trap (NET) formation and drove macrophage polarization toward the CD86-positive M1 pro-inflammatory phenotype. Altogether, our findings implicate that, in the inflamed gingiva, human gingival fibroblasts acquire a senescent phenotype due to oxidative stress-induced DNA and mitochondrial damage, which in turn activate neutrophils and macrophages through the secretion of SASP factors.

RXRα/MR signaling promotes diabetic kidney disease by facilitating renal tubular epithelial cells senescence and metabolic reprogramming

Cell senescence and metabolic reprogramming are significant features of diabetic kidney disease (DKD). However, the underlying mechanisms between cell senescence and metabolic reprogramming are poorly defined. Here, we report that retinoid X receptor α (RXRα), a key nuclear receptor transcription factor, regulates cell senescence and metabolic reprogramming in DKD. Through high-throughput sequencing, bioinformatic analysis and experimental validation, we confirmed the critical role of RXRα in promoting cell senescence and metabolic dysregulation in renal tubular epithelial cells (RTECs) induced by lipid overload. In vivo, in situ injection of AAV9-shRxra into the kidney reduced proteinuria, RTECs senescence and insulin resistance in DKD mice. In vitro, knockdown of RXRα markedly improved G2/M phase arrest and suppressed the expression of senescence-associated secretory phenotypes (SASPs). Protein-protein interaction (PPI) analysis and unbiased bioinformatics were employed to identify the direct interactions between RXRα and the mineralocorticoid receptor (MR), which were subsequently validated through coimmunoprecipitation. Gene network analysis revealed the collaborative regulatory role of RXRα and MR in RTECs senescence. In an accelerated aging mouse model, treatment with a MR antagonist has been shown to inhibite the RXRα/MR signaling, improve RTECs senescence, and reduce interstitial fibrosis and lipid deposition in the kidneys. These findings indicate that inhibition of RXRα/MR signaling could alleviate cell senescence during metabolic disorders. Thus, our study revealed that RXRα/MR signaling serves as a critical regulatory factor mediating the crosstalk between cell senescence and metabolic reprogramming, shedding light on a novel mechanism for targeting cell senescence and metabolic dysregulation in DKD.

Restoration of hair follicle inductive properties by depletion of senescent cells.

Senescent cells secrete a senescence-associated secretory phenotype (SASP), which can induce senescence in neighboring cells. Human dermal papilla (DP) cells lose their original hair inductive properties when expanded invitro, and rapidly accumulate senescent cells in culture. Protein and RNA-seq analysis revealed an accumulation of DP-specific SASP factors including IL-6, IL-8, MCP-1, and TIMP-2. We found that combined senolytic treatment of dasatinib and quercetin depleted senescent cells, and reversed SASP accumulation and SASP-mediated repressive interactions in human DP culture, resulting in an increased Wnt-active cell population. In hair reconstitution assays, senolytic-depleted DP cells exhibited restored hair inductive properties by regenerating de novo hair follicles (HFs) compared to untreated DP cells. In 3D skin constructs, senolytic-depleted DP cells enhanced inductive potential and hair lineage specific differentiation of keratinocytes. These data revealed that senolytic treatment of cultured human DP cells markedly increased their inductive potency in HF regeneration, providing a new rationale for clinical applications of senolytic treatment in combination with cell-based therapies.

Inhibition of the E3 ligase UBR5 stabilizes TERT and protects vascular organoids from oxidative stress

BackgroundExcessive oxidative stress is known to cause endothelial dysfunction and drive cardiovascular diseases (CVD). While telomerase reverse transcriptase (TERT) shows protective effects against oxidative stress in rodents and is associated to human flow-mediated dilation in CVD, its regulatory mechanisms in human vascular systems under pathological oxidative stress require further investigation.MethodsHuman induced pluripotent stem cells (hiPSCs) were used to create vascular organoids (VOs). These VOs and human umbilical vein endothelial cells (HUVECs) were subjected to oxidative stress through both hydrogen peroxide (H2O2) and oxidized low-density lipoprotein (oxLDL) models. The effects of TERT overexpression by inhibition of the ubiquitin protein ligase E3 component N-recognin 5 (UBR5) on reactive oxygen species (ROS)-induced vascular injury and cellular senescence were assessed using neovascular sprouting assays, senescence-associated β-galactosidase (SA-β-Gal) staining, and senescence-associated secretory phenotype (SASP) assays.ResultsROS significantly impaired VO development and endothelial progenitor cell (EPC) angiogenesis, evidenced by reduced neovascular sprouting and increased senescence markers, including elevated SA-β-Gal activity and SASP-related cytokine levels. Overexpression of TERT counteracted these effects, restoring VO development and EPC function. Immunoprecipitation-mass spectrometry identified UBR5 as a critical TERT regulator, facilitating its degradation. Inhibition of UBR5 stabilized TERT, improving VO angiogenic capacity, and reducing SA-β-Gal activity and SASP cytokine levels.ConclusionsInhibiting UBR5 stabilizes TERT, which preserves EPC angiogenic capacity, reduces VO impairment, and delays endothelial cell senescence under oxidative stress. These findings highlight the potential of targeting UBR5 to enhance vascular health in oxidative stress-related conditions.Graphical

Decoding senescence of aging single cells at the nexus of biomaterials, microfluidics, and spatial omics.

Aging has profound effects on the body, most notably an increase in the prevalence of several diseases. An important aging hallmark is the presence of senescent cells that no longer multiply nor die off properly. Another characteristic is an altered immune system that fails to properly self-surveil. In this multi-player aging process, cellular senescence induces a change in the secretory phenotype, known as senescence-associated secretory phenotype (SASP), of many cells with the intention of recruiting immune cells to accelerate the clearance of these damaged senescent cells. However, the SASP phenotype results in inducing secondary senescence of nearby cells, resulting in those cells becoming senescent, and improper immune activation resulting in a state of chronic inflammation, called inflammaging, in many diseases. Senescence in immune cells, termed immunosenescence, results in further dysregulation of the immune system. An interdisciplinary approach is needed to physiologically assess aging changes of the immune system at the cellular and tissue level. Thus, the intersection of biomaterials, microfluidics, and spatial omics has great potential to collectively model aging and immunosenescence. Each of these approaches mimics unique aspects of the body undergoes as a part of aging. This perspective highlights the key aspects of how biomaterials provide non-cellular cues to cell aging, microfluidics recapitulate flow-induced and multi-cellular dynamics, and spatial omics analyses dissect the coordination of several biomarkers of senescence as a function of cell interactions in distinct tissue environments. An overview of how senescence and immune dysregulation play a role in organ aging, cancer, wound healing, Alzheimer's, and osteoporosis is included. To illuminate the societal impact of aging, an increasing trend in anti-senescence and anti-aging interventions, including pharmacological interventions, medical procedures, and lifestyle changes is discussed, including further context of senescence.

Autophagy in the Cellular Consequences of Tobacco Smoking: Insights into Senescence.

Smoking is a significant contributing factor to the development of many complex diseases. One of the most important stimuli for aging in the human body is constant exposure to environmental factors such as cigarette smoke. Free radicals in cigarette smoke cause reactive oxygen species production at the cellular level and induce inflammatory responses. The respiratory system of smokers exhibits age-related characteristics, such as enhanced oxidative stress, accumulated damaged proteins, and increased inflammation. Autophagy is triggered by tobacco smoke as a protective mechanism to prevent and reduce molecular stress. However, smoking can interfere with the normal functioning of autophagy in various ways. Smoking-induced impairment of autophagy leads to irreversible cellular damage accumulation, causing cells to undergo cellular aging or senescence. Senescent cells lose their ability to divide and display a distinct secretory phenotype called the senescence-associated secretory phenotype (SASP) and produce numerous growth factors, immune modulators, and inflammatory cytokines. This review discusses the effects of tobacco smoke exposure on autophagy alteration, cellular aging, and senescence induction in exposed animal models, as well as in exposed epithelial and immune cells in the body.

Post-traumatic stress disorder: Cerebral and extracerebral processing of traumatic memories and treatment strategies

Post-traumatic stress disorder (PTSD) is a severe neuropsychiatric condition characterized by anxiety-related symptoms, including intrusive memories. However, the exact anatomic location of traumatic memories remains unclear. Traumatic imagery may involve the amygdala and posterior cingulate cortex, rather than the hippocampus. Besides the central nervous system, cells and even proteins can process information and store memories. For instance, >36% of cardiac transplant recipients inherit donor personality traits, emphasizing that tissues can store and recall memories. Moreover, physical therapists mention “musculofascial memories,” that is, the ability of muscles and fascia to retain the memory of past injuries and adapt their function accordingly. Immune cells record previous infections, demonstrating the broader perspective of memory storage in the body. At the cellular level, psychological stress induces premature cellular senescence, a survival program characterized by proliferation arrest; resistance to apoptosis; and a toxic secretome known as the senescence-associated secretory phenotype (SASP). SASP contains brain-derived neurotropic factor (BDNF), a neurotrophin linked to fear memory that is frequently elevated in the peripheral blood of patients with PTSD. Endothelial cells (ECs), the tiles paving the lumen of large and small vessels, age earlier than other cells in patients with severe mental illness, including PTSD. Senescent ECs release SASP directly into the systemic circulation, spreading senescence throughout the body. In this narrative review, we hypothesize that ECs store traumatic memories and SASP-associated BDNF activates traumatic imagery. We also discuss membrane lipid replacement, mitochondrial transplantation and transfer, and several natural and synthetic compounds that may counteract endothelial senescence and SASP.

Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation

BackgroundMicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence.ResultsWild-type (WT) HFD-fed mice exhibited increased body weight, impaired locomotor activity, and cognitive decline compared to low-fat diet (LFD) controls. In the brain, HFD induced senescence markers (p16, p21), β-galactosidase activity (β-gal) of microglia, and increased expression of senescence associated secretory phenotype (SASP) cytokines (Il1b, Il18, Tnf, Il6) in activated hypothalamic microglia. In the liver, increased p21 and SASP cytokines were detected, although p16 and β-gal levels remained unchanged. Importantly, miR-146a expression was significantly downregulated in the hypothalamus following HFD exposure in WT mice, while miR-146a knockout (Mir146a-/-) mice subjected to HFD showed augmented hypothalamic senescence characterized by higher levels of p16, p21, and β-gal + microglial cells as compared to WT mice. The SASP profile remained similar between Mir146a-/- HFD and WT HFD mice. Among miR-146a target genes, smad4 was upregulated the hypothalamus of HFD-fed mice, with a more pronounced increase in the hypothalamus of HFD-fed Mir146a-/- mice. Further, treatment with Elo upregulated miR-146a expression in both the hypothalamus and the liver, lowered body weight and improved cognitive function, while reducing senescence markers and SASP cytokines in WT HFD mice. These effects were absent in Mir146a-/- HFD mice when treated with Elo, indicating the dependence of Elo’s therapeutic efficacy on miR-146a.ConclusionElocalcitol prevents development of senescence in microglia via modulation of miR-146a expression, while miR-146a provides protection against HFD-induced cellular senescence in the hypothalamus most probably via inhibition of TGF/Smad4 pathway. These findings highlight Elo and miR-146a as promising therapeutic candidates for ameliorating obesity-related neuroinflammation and senescence.

Anti-aging effect of extracellular vesicles from mesenchymal stromal cells on senescence-induced chondrocytes in osteoarthritis.

Age is the most important risk factor for degenerative diseases such as osteoarthritis (OA). It is associated with the accumulation of senescent cells in joint tissues that contribute to the pathogenesis of OA, in particular through the release of senescence-associated secretory phenotype (SASP) factors. Mesenchymal stromal cells (MSCs) and their derived extracellular vesicles (EVs) are promising treatments for OA. However, the senoprotective effects of MSC-derived EVs in OA have been poorly investigated. Here, we used EVs from human adipose tissue-derived MSCs (ASC-EVs) in two models of inflammaging (IL1β)- and DNA damage (etoposide)-induced senescence in OA chondrocytes. We showed that the addition of ASC-EVs was effective in reducing senescence parameters, including the number of SA-β-Gal-positive cells, the accumulation of γH2AX foci in nuclei and the secretion of SASP factors. In addition, ASC-EVs demonstrated therapeutic efficacy when injected into a murine model of OA. Several markers of senescence, inflammation and oxidative stress were decreased shortly after injection likely explaining the therapeutic efficacy. In conclusion, ASC-EVs exert a senoprotective function both in vitro, in two models of induced senescence in OA chondrocytes and, in vivo, in the murine model of collagenase-induced OA.

Cell cycle inhibitors activate the hypoxia-induced DDX41/STING pathway to mediate antitumor immune response in liver cancer.

Cell cycle inhibitors have a long history as cancer treatment. Here, we report that these inhibitors combated cancer partially via the stimulator of IFN genes (STING) signaling pathway. We demonstrated that paclitaxel (microtubule stabilizer), palbociclib (cyclin-dependent kinase 4/6 inhibitor), and AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anticancer functions beyond arresting the cell cycle. They consistently caused cytosolic DNA accumulation and DNA damage, which inadvertently triggered the cytosolic DNA sensor DEAD-box helicase 41 (DDX41) and activated STING to secrete pro-inflammatory senescence-associated secretory phenotype factors (SASPs). Interestingly, we found that DDX41 was a transcriptional target of HIF. Hypoxia induced expression of DDX41 through HIF-1, making hypoxic hepatocellular carcinoma (HCC) cells more sensitive to the antimitotic agents in STING activation and SASP production. The SASPs triggered immune cell infiltration in tumors for cancer clearance. The treatment with cell cycle inhibitors, especially paclitaxel, extended survival by perturbing mouse HCC growth when used in combination with anti-PD-1. We observed a trend that paclitaxel suppressed Sting wild-type HCC more effectively than Sting-KO HCC, suggesting that STING might contribute to the antitumor effects of paclitaxel. Our study revealed the immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested combined treatment with immunotherapy as a potential therapeutic approach.

Abstract IA027: Age-related stromal changes drive breast cancer tumor progression

Abstract Age is the single largest risk factor for the development of cancer, but how age impacts the molecular mechanisms that drive cancer remain poorly understood. While it is clear that age-related accumulation of cell autonomous mutations contributes to tumorigenesis, the central role age-related changes in the tumor microenvironment play in the transformation process is becoming more fully appreciated. Underscoring the importance of an aged microenvironment in cancer development are findings that senescent fibroblasts, which accumulate with age, directly stimulate preneoplastic and neoplastic cell growth and tumor progression. Investigations into how senescent fibroblasts promote tumorigenesis revealed that they express a plethora of growth factors, extracellular matrix remodeling enzymes, chemokines, and cytokines collectively referred to as the senescence associated secretory phenotype (SASP). Chemotherapy induces similar changes that can negatively impact a patient’s quality of life. We will discuss how these changes impact tumor progression and therapy-induced bone loss. Citation Format: Sheila A. Stewart. Age-related stromal changes drive breast cancer tumor progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA027.

Abstract A043: Senescent CAFs modulate tumor immunity and promote breast cancer progression

Abstract Cellular senescence is characterized by a series of markers such as p16INKA4(p16) positivity and a distinctive profile of secretory factors including mitogens, cytokines, and extracellular matrix (ECM) proteins that are collectively recognized as senescence-associated secretory phenotype (SASP). Interestingly, high p16 positivity in stroma strongly correlates with ductal carcinoma in situ (DCIS) recurrence, raising the possibility that p16+ senescent stromal cells contribute to breast cancer progression. To explore the hypothesis, we carried out single-cell RNA sequencing (scRNA-seq) analyses of murine and human HER2+/ER+/TNBC tumor samples and found that senescence was restricted to a specific cancer-associated fibroblasts (CAF) subpopulation that expresses numerous SASP factors that could impact tumor immunosurveillance, including cytokine SASP factors and ECM SASP factors such as collagens. We refer to these cells as senescent CAFs (senCAFs). To investigate how senCAFs impact tumorigenesis, we crossed MMTV-PyMT (PyMT) mice that spontaneously develop mammary tumors to INK-ATTAC (INK) mice, which allows selective elimination of p16+ senescent cells. Depletion of senCAFs in PyMT/INK mice led to significantly delayed tumor onset and changes in various tumor-infiltrating immune cells including natural killer (NK) cells, both of which could be recapitulated by treating PyMT mice with a senolytic drug. Monoclonal antibody- mediated NK cell depletion in the PyMT model further indicated that NK cells are indispensable for senCAF’s tumor-promoting effect. Finally, our bulk RNA-sequencing and cytotoxicity assays revealed that ECM derived from senescent but not cycling myofibroblastic mammary fibroblasts potently inhibited NK cell killing of tumor cells. Importantly, PyMT mice treated with Losartan (DuP-753), an inhibitor for collagen I synthesis, showed lower tumor burden and improved tumor-infiltrating NK cell status. Together our data highlight that senCAFs contribute to mammary gland tumorigenesis by modulating tumor ECM and immunity and suggest that senolytic treatment may limit breast cancer progression. Citation Format: Jiayu Ye, John M. Baer, Douglas V. Faget, Vasilios A. Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Erik Knudsen, Agnieszka Witkiewicz, Robert S. Powers, Gregory D. Longmore, David G. DeNardo, Sheila A. Stewart. Senescent CAFs modulate tumor immunity and promote breast cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A043.

The Mechanistic Link Between Tau-Driven Proteotoxic Stress and Cellular Senescence in Alzheimer's Disease.

In Alzheimer's disease (AD), tau dissociates from microtubules (MTs) due to hyperphosphorylation and misfolding. It is degraded by various mechanisms, including the 20S proteasome, chaperone-mediated autophagy (CMA), 26S proteasome, macroautophagy, and aggrephagy. Neurofibrillary tangles (NFTs) form upon the impairment of aggrephagy, and eventually, the ubiquitin chaperone valosin-containing protein (VCP) and heat shock 70 kDa protein (HSP70) are recruited to the sites of NFTs for the extraction of tau for the ubiquitin-proteasome system (UPS)-mediated degradation. However, the impairment of tau degradation in neurons allows tau to be secreted into the extracellular space. Secreted tau can be monomers, oligomers, and paired helical filaments (PHFs), which are seeding competent pathological tau that can be endocytosed/phagocytosed by healthy neurons, microglia, astrocytes, oligodendrocyte progenitor cells (OPCs), and oligodendrocytes, often causing proteotoxic stress and eventually triggers senescence. Senescent cells secrete various senescence-associated secretory phenotype (SASP) factors, which trigger cellular atrophy, causing decreased brain volume in human AD. However, the molecular mechanisms of proteotoxic stress and cellular senescence are not entirely understood and are an emerging area of research. Therefore, this comprehensive review summarizes pertinent studies that provided evidence for the sequential tau degradation, failure, and the mechanistic link between tau-driven proteotoxic stress and cellular senescence in AD.