Role of ACER2 in cancer chemoresistance and metastasis

ACER2在癌症化疗耐药和转移中的作用

• 批准号: 10650378
• 负责人: CUNGUI MAO
• 金额: $ 49.88万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650378
• 关键词: Adjuvant Chemotherapy; Apoptosis; Bone Marrow; Brain; Breast; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer therapy; Breast cancer metastasis; Cancer Etiology; Cancer Model; Cell Death; Cell Proliferation; Cell Survival; Cells; Ceramidase; Ceramides; Cessation of life; Chemoresistance; Chemotherapy-Oncologic Procedure; Circulation; Clinical; Clinical Management; DNA Damage; Data; Dose; Down-Regulation; Doxorubicin; Eligibility Determination; Family; Fatty acid glycerol esters; Future; Genes; Goals; Homeostasis; Hydrolysis; Immune response; Ionizing radiation; Knockout Mice; Lipids; Liver; Lung; Lymphangiogenesis; Malignant Neoplasms; Mammals; Mammary Gland Parenchyma; Mediating; Metastatic Neoplasm to the Lung; Metastatic/Recurrent; Modality; Molecular; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Phosphorylation; Proliferating; Publishing; Recurrence; Refractory; Role; Saccharomyces cerevisiae; Scheme; Site; Sphingosine; TP53 gene; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor Angiogenesis; Tumor Promotion; Up-Regulation; Woman; Yeasts; advanced breast cancer; angiogenesis; cancer stem cell; chemotherapeutic agent; chemotherapy; combinatorial; genotoxicity; improved; inflammatory breast cancer; inhibitor; malignant breast neoplasm; mammary; member; mouse alkaline ceramidase; mouse model; neoplastic cell; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pre-clinical; restraint; small molecule inhibitor; sphingosine 1-phosphate; sphingosine kinase; stem cell survival; tumor; tumor growth; tumorigenic

Neoadjuvant chemotherapy (NAC) has become an increasingly popular treatment approach for breast cancer (BC) patients. It enables locally advanced and inflammatory BC patients to be eligible for breast conservative surgery. However, emerging evidence suggests that preoperative NAC may paradoxically increase the risk of BC cancer chemoresistance and progression, thus limiting its therapeutic efficacy. The specific goals of this application are to define a novel role for alkaline ceramidase 2 (ACER2) in mediating NAC-induced chemoresistance and metastasis of BC and to develop this concept into novel therapeutic approaches to improving BC therapy. ACER2 is a member in the alkaline ceramidase family that we identified initially from the yeast Saccharomyces cerevisiae and then from mammals. ACER2 catalyzes the hydrolysis of ceramide to generate sphingosine (SPH), which is immediately converted to sphingosine-1-phosphate (S1P), a bioactive lipid that has been implicated in tumor angiogenesis and lymphangiogenesis, protumoral immune responses, and cancer stem cell survival. Our preliminary studies demonstrate that doxorubicin (DOX), a chemotherapeutic agent commonly used in BC patients, induces a marked increase in the levels of S1P in in the tumor, primary site of the tumor (mammary fat pads), and major metastatic tissues of BC (brain, bone marrow, liver, and lungs) in a syngeneic mouse model of BC. We further show that knocking out the mouse alkaline ceramidase 2 gene (Acer2) from host cells markedly inhibits DOX-induced increase in the levels of S1P in the tumor and the aforementioned tissues, robustly augments DOX-induced tumor growth inhibition, and inhibits DOX-induced pulmonary metastasis of BC. These compelling results support our hypothesis that NAC-induced upregulation of the ACER2/S1P pathway mediates BC chemoresistance and metastasis. As a further corollary, we hypothesize that blocking the ACER2/S1P pathway with an ACER2 inhibitor (ACER2i) will improve the therapeutic efficacy of chemotherapeutic agents against BC by mitigating chemotherapy-induced chemoresistance and metastasis of BC. To test these hypotheses, we will 1) establish that ACER2 mediates NAC-induced chemoresistance and metastasis of BC (Aim 1); 2) Define the molecular and cellular mechanisms by ACER2 mediates NAC-induced chemoresistance and metastasis (Aim 2); and 3) Establish that targeting ACER2 with its small molecule inhibitor (ACER2i) would mitigate NAC-induced chemoresistance and metastasis of BC and thereby improves NAC of BC (Aim 3). Successful completion of these aims will 1) validate the pathological role of the ACER2/S1P pathway in cancer chemoresistance, metastasis, and recurrence; and 2) provide a proof of concept that targeting the ACER2 pathway would improve BC chemotherapy. Given the poor clinical outcome of patients with most cancers, these studies may have widespread impact on the clinical management of these patients.

新辅助化疗（NAC）已成为越来越流行的乳腺癌治疗方法 （BC）患者。它使局部晚期和炎症性 BC 患者有资格接受乳房保守治疗 外科手术。然而，新出现的证据表明，术前 NAC 可能会增加以下风险： BC癌症的化疗耐药性和进展，从而限制了其治疗效果。本次活动的具体目标 该申请旨在确定碱性神经酰胺酶 2 (ACER2) 在介导 NAC 诱导的过程中的新作用 BC 的化疗耐药性和转移，并将这一概念发展成新的治疗方法 改善 BC 治疗。 ACER2 是碱性神经酰胺酶家族的成员，我们最初从 酿酒酵母，然后来自哺乳动物。 ACER2 催化神经酰胺水解 生成鞘氨醇 (SPH)，立即转化为 1-磷酸鞘氨醇 (S1P)，一种生物活性脂质 与肿瘤血管生成和淋巴管生成、促肿瘤免疫反应以及 癌症干细胞存活。我们的初步研究表明阿霉素（DOX）是一种化疗药物 BC 患者常用的药物，可诱导肿瘤、原发性肿瘤中的 S1P 水平显着升高。 肿瘤部位（乳腺脂肪垫）和 BC 主要转移组织（脑、骨髓、肝脏和肺） 在 BC 同基因小鼠模型中。我们进一步证明，敲除小鼠碱性神经酰胺酶 2 基因 来自宿主细胞的 (Acer2) 显着抑制 DOX 诱导的肿瘤和细胞中 S1P 水平的增加 上述组织，强烈增强 DOX 诱导的肿瘤生长抑制，并抑制 DOX 诱导的肿瘤生长 BC 肺转移。这些令人信服的结果支持了我们的假设，即 NAC 诱导的上调 ACER2/S1P 通路介导 BC 化疗耐药和转移。作为进一步的推论，我们 假设用 ACER2 抑制剂 (ACER2i) 阻断 ACER2/S1P 通路将改善 化疗药物通过减轻化疗引起的乳腺癌的治疗效果 BC的化疗耐药性和转移。为了检验这些假设，我们将 1) 确定 ACER2 介导 NAC 诱导的 BC 化疗耐药和转移（目标 1）； 2) 定义分子和细胞机制 ACER2 介导 NAC 诱导的化疗耐药性和转移（目标 2）； 3) 确定目标 ACER2 及其小分子抑制剂 (ACER2i) 将减轻 NAC 诱导的化疗耐药和转移 BC 的 NAC，从而提高 BC 的 NAC（目标 3）。成功完成这些目标将 1) 验证 ACER2/S1P 通路在癌症化疗耐药、转移和复发中的病理作用；和 2) 提供了一个概念证明，即靶向 ACER2 通路将改善 BC 化疗。考虑到穷人 大多数癌症患者的临床结果，这些研究可能对临床产生广泛的影响 对这些患者的管理。