Role of senescence in multiple myeloma tumorigenesis

衰老在多发性骨髓瘤肿瘤发生中的作用

• 批准号: 10659259
• 负责人: Thomas Levin Geiser Andersen
• 金额: $ 39.87万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659259
• 关键词: Ablation; Acute; Age; Aging; Area; Automobile Driving; Benign; Benign Monoclonal Gammopathies; Biopsy; Bone Marrow; Cell Aging; Cell Senescence Induction; Cells; Cellular Stress; Characteristics; Chromosome abnormality; Clinical Trials; Clonal Evolution; DNA; DNA Transposable Elements; Data; Data Set; Development; Diagnosis; Disease Progression; Evaluation; Exhibits; Gene Deletion; Gene Expression; Gene Mutation; Genes; Genetic; Genomic Instability; Goals; Growth; Hematologic Neoplasms; Hematopoietic Neoplasms; Human; Hybrids; In Vitro; Incidence; Inflammation; Inflammatory; Interferons; Malignant Neoplasms; Mediating; Methylation; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Mutation; Nucleic Acids; Obesity; Oncogene Activation; Oncogenes; Oncogenic; Pathology; Patients; Phenotype; Plasma Cell Neoplasm; Plasma Cells; Precancerous Conditions; RNA; Risk Factors; Role; Single-Stranded DNA; Stains; Techniques; Testing; Translating; United States; aged; bone; cell transformation; in vivo; mouse model; neoplastic cell; permissiveness; pharmacologic; premalignant; prevent; promoter; response; senescence; success; therapeutic development; tool; tumor; tumorigenesis; tumorigenic

Abstract Multiple myeloma (MM) is an incurable, plasma cell (PC) malignancy that progresses from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Although MGUS and SMM PCs exhibit similar oncogenic mutations to MM PCs, they are considered benign and it is unclear what drives tumorigenesis of these pre-malignant PCs. Aging is the primary risk factor for cancers, including MM; it is therefore unsurprising that aging and tumorigenesis exhibit shared mechanisms. One of these shared mechanisms is cellular senescence. Cellular senescence is induced in response to cellular stress, such as oncogenic mutations, and activates growth arrest to prevent tumor formation. However, the accumulation of senescent cells with age contributes to aging pathologies, including cancer. Although deletion or inhibition of genes necessary for senescence induction leads to tumor formation, elimination of senescent cells reduces tumor incidence in aged mice. This suggests that senescent cell accumulation may create a pro- tumorigenic microenvironment; alternatively, pre-tumor cells may themselves be senescent and targeted by senescent cell elimination strategies. In support of this, we found that both MGUS and SMM PCs have enrichment of cellular senescence genes. In addition, SMM PCs show characteristics of late-senescence, including an interferon senescence-associated secretory phenotype (SASP) and the accumulation of cytosolic ssDNA and DNA:RNA hybrids that are associated with increased genomic instability. These findings support a role for PC senescence in monoclonal gammopathies, and suggest a potential mechanism that may ultimately drive tumorigenesis. Importantly, clonal PCs have also been shown to induce senescence in the bone marrow microenvironment (BMME), suggesting additional mechanisms by which senescence may promote a permissive niche for MM tumorigenesis. Thus, we hypothesize that senescence within PCs and their proximate BMME drives progression of MGUS/SMM to MM. In this application, we propose to use genetic mouse models and human patient-derived cells and bone biopsies to ascertain the mechanisms by which senescence drives tumorigenesis through both direct effects on pre-tumor cells and on the BMME. The results of these studies will define a role for senescence, a common aging mechanism, in tumorigenesis. We anticipate that these findings can be rapidly translated to clinical trials targeting the progression of monoclonal gammopathies to MM.

抽象的 多发性骨髓瘤 (MM) 是一种无法治愈的浆细胞 (PC) 恶性肿瘤，由前体细胞进展而来 意义未明的单克隆丙种球蛋白病 (MGUS) 和冒烟型多发性骨髓瘤 （SMM）。尽管 MGUS 和 SMM PC 表现出与 MM PC 相似的致癌突变，但它们被认为 良性的，目前尚不清楚是什么驱动了这些癌前 PC 的肿瘤发生。衰老是主要危险因素 用于癌症，包括多发性骨髓瘤；因此，衰老和肿瘤发生表现出共同的机制也就不足为奇了。 这些共同机制之一是细胞衰老。细胞衰老是响应细胞 压力，例如致癌突变，并激活生长停滞以防止肿瘤形成。然而， 随着年龄的增长，衰老细胞的积累会导致衰老病理，包括癌症。虽然删除了 或抑制衰老诱导所需的基因导致肿瘤形成，消除衰老 细胞可降低老年小鼠的肿瘤发病率。这表明衰老细胞的积累可能会产生亲 致瘤微环境；或者，肿瘤前细胞本身可能已经衰老并被靶向 衰老细胞消除策略。为了支持这一点，我们发现 MGUS 和 SMM PC 都具有 细胞衰老基因的富集。此外，SMM PC表现出晚衰老的特征， 包括干扰素衰老相关的分泌表型（SASP）和胞质的积累 ssDNA 和 DNA:RNA 杂交体与基因组不稳定性增加有关。这些发现支持 PC 衰老在单克隆丙种球蛋白病中的作用，并提出了最终可能的潜在机制 驱动肿瘤发生。重要的是，克隆 PC 也被证明可以诱导骨髓衰老 微环境（BMME），表明衰老可能促进宽容的其他机制 MM 肿瘤发生的利基。因此，我们假设 PC 及其邻近的 BMME 内的衰老 推动 MGUS/SMM 进展为 MM。在此应用中，我们建议使用遗传小鼠模型和 人类患者来源的细胞和骨活检以确定衰老驱动机制 通过对肿瘤前细胞和 BMME 的直接影响来实现肿瘤发生。这些研究的结果将 定义衰老（一种常见的衰老机制）在肿瘤发生中的作用。我们预计这些发现 可以快速转化为针对单克隆丙种球蛋白病进展为 MM 的临床试验。

项目成果

Metastatic infiltration of nervous tissue and periosteal nerve sprouting in multiple 1 myeloma induced bone pain

多发性骨髓瘤引起的骨痛中神经组织和骨膜神经萌发的转移性浸润

• 发表时间: 1970-01-01
• 作者: Marta Diaz;Oana Palasca;Tim T. Nemler;Didde M Thygesen;Saldaña;Juan A Vázquez;Lizeth Gomez;L. Jensen;H.R. Evans;R. E. Andrews;Aritri M;al;al;D. Neves;P. Mehlen;James P Caruso;P. Dougherty;Theodore John Price;A. Chantry;M. Lawson;L. Thomas;Andersen;J. M. Jiménez;A. Heegaard
• 通讯作者: A. Heegaard

Disturbed bone marrow adiposity in patients with Cushing's syndrome and glucocorticoid- and postmenopausal- induced osteoporosis.

库欣综合征以及糖皮质激素和绝经后诱发的骨质疏松症患者的骨髓肥胖受到干扰。

• 发表时间: 2023
• 作者: Sørensen, Nina N;Andreasen, Christina M;Jensen, Pia R;Hauge, Ellen M;Bollerslev, Jens;Delaissé, Jean;Kassem, Moustapha;Jafari, Abbas;Diaz;Andersen, Thomas L
• 通讯作者: Andersen, Thomas L

Bone marrow adipocytes provide early sign for progression from MGUS to multiple myeloma.

骨髓脂肪细胞提供从 MGUS 进展为多发性骨髓瘤的早期迹象。

• 发表时间: 2024-01-16
• 作者: El;Leka, Benedeta;Mustapha, Fatima;Gundesen, Michael Tveden;Hinge, Maja;Lund, Thomas;Andersen, Thomas L;Diaz;Jafari, Abbas
• 通讯作者: Jafari, Abbas