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）已成为一种越来越受欢迎的乳腺癌治疗方法 (BC)患者它使局部晚期和炎症性BC患者有资格进行乳房保守治疗 手术然而，新出现的证据表明，术前NAC可能会矛盾地增加 BC癌症的化学抗性和进展，从而限制了其治疗效果。具体目标是 应用是为了确定碱性神经酰胺酶2（ACER 2）在介导NAC诱导的 化疗耐药性和转移的BC，并将这一概念发展成新的治疗方法， 改善BC疗法。ACER 2是碱性神经酰胺酶家族中的一员，我们最初从 酵母酿酒酵母，然后从哺乳动物。ACER 2催化神经酰胺水解， 产生鞘氨醇（SPH），立即转化为鞘氨醇-1-磷酸（S1 P），一种生物活性脂质 它与肿瘤血管生成和淋巴管生成、肿瘤前免疫反应以及 癌症干细胞存活率我们的初步研究表明，阿霉素（DOX），一种化疗药物， 通常用于BC患者的药物，诱导肿瘤中S1 P水平的显著增加，原发性 肿瘤部位（乳腺脂肪垫）和BC的主要转移组织（脑、骨髓、肝和肺） 在BC的同基因小鼠模型中。我们进一步表明，敲除小鼠碱性神经酰胺酶2基因， （Acer 2）显著抑制肿瘤中DOX诱导的S1 P水平的增加， 在上述组织中，强力增强DOX诱导的肿瘤生长抑制，并抑制DOX诱导的肿瘤生长抑制。 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 ACER 2/S1 P通路介导了乳腺癌的耐药性和转移。作为进一步的推论，我们 假设用ACER 2抑制剂（ACER 2 i）阻断ACER 2/S1 P通路将改善 化疗剂通过减轻化疗诱导的 化疗耐药性和转移。为了验证这些假设，我们将1）确定ACER 2介导 NAC诱导的BC化疗耐药和转移（目的1）; 2）明确分子和细胞机制 通过ACER 2介导NAC诱导的化学抗性和转移（目的2）;和3）建立靶向 ACER 2及其小分子抑制剂（ACER 2 i）可减轻NAC诱导的化疗耐药性和转移 BC的NAC，从而改善BC的NAC（目的3）。这些目标的成功实现将1）验证 ACER 2/S1 P通路在癌症化学抗性、转移和复发中的病理学作用;和2） 提供了靶向ACER 2通路将改善BC化疗的概念证据。鉴于穷人 大多数癌症患者的临床结局，这些研究可能对临床 管理这些病人。