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)已成为乳腺癌的一种日益流行的治疗方法 (BC)病人。它使局部晚期和炎症性BC患者有资格接受保乳手术 做手术。然而，新出现的证据表明，术前NAC可能会矛盾地增加 BC癌的化疗耐药和进展，从而限制其治疗效果。这一行动的具体目标 应用是确定碱性神经酰胺酶2(ACER2)在介导NAC诱导的新作用中的作用 结直肠癌的化疗耐药和转移，并将这一概念发展为新的治疗方法 改进BC疗法。ACER2是碱性神经酰胺酶家族中的一个成员，我们最初从 酵母是酿酒酵母，然后是哺乳动物。ACER2催化神经酰胺水解酶 产生鞘氨醇(SPH)，它会立即转化为生物活性脂质-1-磷酸鞘氨醇(S1P) 这与肿瘤血管生成和淋巴管生成、前列腺癌免疫反应以及 癌症干细胞存活。我们的初步研究表明，阿霉素(DOX)，一种化疗药物 在BC患者中常用的药物，会诱导肿瘤中S1P水平显著升高，原发 肿瘤的部位(乳房脂肪垫)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。我们进一步证明敲除小鼠碱性神经酰胺酶2基因 宿主细胞(Acer2)显著抑制DOX诱导的肿瘤组织中S1P水平的升高和 上述组织，有力地增强了DOX诱导的肿瘤生长抑制，并抑制了DOX诱导的 卑诗省的肺转移。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通路参与了BC的化疗耐药和转移。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 化疗药物减轻化疗诱导的结直肠癌疗效观察 大肠埃希菌耐药与转移的关系。为了检验这些假说，我们将1)确定ACER2在 NAC诱导的BC细胞化疗耐药和转移(目标1)；2)确定分子和细胞机制 ACER2介导NAC诱导的化疗耐药和转移(目标2)；以及3)建立靶向 ACER2及其小分子抑制剂(ACER2i)可减轻NAC诱导的化疗耐药和转移 从而提高不列颠哥伦比亚省的NAC(目标3)。成功完成这些目标将1)验证 ACER2/S1P通路在肿瘤化疗耐药、转移和复发中的病理作用 提供靶向ACER2通路将改善BC化疗的概念证据。考虑到穷人 大多数癌症患者的临床结局，这些研究可能会对临床产生广泛的影响 这些病人的管理。