Metabolic adaptation in residual triple negative breast cancer following chemotherapy

化疗后残留三阴性乳腺癌的代谢适应

基本信息

批准号：
10585688
负责人：
Gloria Vittone Echeverria
金额：
$ 44.43万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-27 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585688
关键词：
3-Dimensional Address Adjuvant Chemotherapy Adjuvant Therapy Anthracycline Automobile Driving Biopsy Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Cancer Patient Carbon Cell Cycle Cells Cessation of life Chemoresistance Data Disease Equilibrium Face Generations Genetic Goals Guanosine Triphosphate Phosphohydrolases Human Immune system Immunocompetent In Vitro Life Machine Learning Maintenance Malignant Neoplasms Mathematics Measures Mediating Medical Oncology Metabolic Metabolism Mitochondria Mus Neoadjuvant Therapy Oncogenic Optic atrophy 1 Organelles Organoids Oxidative Phosphorylation Patient-Focused Outcomes Patients Phenotype Platinum Play Population Process Protein Dynamics Proteins Recurrence Refractory Regulation Residual Neoplasm Residual state Role Scanning Electron Microscopy Signal Pathway Structure Testing Therapeutic Tissue imaging Transmission Electron Microscopy Transplantation Tumor Burden Visualization chemotherapy high risk improved in vivo inhibitor insight knock-down malignant breast neoplasm mitochondrial genome mitochondrial metabolism mouse model mutant neoplastic cell novel patient derived xenograft model pharmacologic preference response targeted treatment taxane therapeutic target therapy resistant transcriptomics treatment response triple-negative invasive breast carcinoma tumor tumor-immune system interactions tumorigenic

项目摘要

ABSTRACT Oxidative phosphorylation (oxphos), a mitochondrial energy generation process, promotes chemotherapeutic resistance in breast and other cancers. In fact, transplantation of mitochondria from tumorigenic cells into non- tumorigenic cells demonstrated these organelles are necessary and sufficient for aggressive phenotypes of triple negative breast cancer (TNBC) cells. Nearly 50% of TNBC patients treated with neoadjuvant (pre-surgical) chemotherapy (NACT; combined anthracyclines, platinums, and/or taxanes) will harbor substantial residual tumor burden, leading to extremely high risk of recurrence and death4. There are no approved targeted therapies for neoadjuvant treatment of non-BRCA-mutant TNBC. Thus, there is an urgent need to find ways to eradicate residual tumor cells. Furthermore, the mechanisms driving metabolic reprogramming in chemoresistant TNBC are unclear. Our comparisons of serial pre- and post-NACT patient-derived xenograft (PDX) and human TNBC biopsies revealed heightened oxphos signatures in residual tumor cells, and we demonstrated oxphos is a unique therapeutic vulnerability of residual TNBC. We observe significantly higher protein levels of the mitochondrial fusion-driving GTPase optic atrophy 1 (OPA1) in post- vs. pre-NACT TNBC biopsies. Furthermore, high expression of mitochondrial fusion-driving proteins in breast cancer is associated with poor survival. The impact of mitochondrial structure, dictated by the balance of mitochondrial fission and fusion, on metabolism varies highly across tumor types. Despite the importance of mitochondria to metabolism, no studies have addressed how mitochondrial structure impacts metabolic states driving TNBC therapeutic responses. Our preliminary data provide evidence that NACT increases mitochondrial fusion and metabolism in vitro and in vivo. We can increase oxphos and NACT resistance in TNBC cells by genetically or pharmacologically perturbing mitochondrial fission with Mdivi-1, a Drp1 inhibitor. Conversely, perturbation of mitochondrial fusion with MYLS22, an OPA1 inhibitor, decreased oxphos and NACT resistance. We hypothesize OPA1-driven mitochondrial fusion mediates an NACT-induced metabolic switch to promote chemoresistance in TNBC cells. To address this, our specific aims are to: 1) Determine if mitochondrial fusion is responsible for chemotherapy- induced oxphos in TNBC, and 2) Target and quantify mitochondrial fusion in residual TNBC mouse models and serial patient biopsies. These results will increase our mechanistic understanding of regulation of the mitochondrial life, as well as mechanisms driving metabolic adaptations in TNBC. Furthermore, our findings will provide additional metabolic therapeutic targets to overcome chemoresistance in residual TNBCs.

抽象的氧化磷酸化 (oxphos) 是一种线粒体能量生成过程，可促进化疗对乳腺癌和其他癌症的抵抗力。事实上，将致瘤细胞的线粒体移植到非肿瘤细胞中致瘤细胞证明这些细胞器对于三重细胞的侵袭性表型是必要且充分的阴性乳腺癌（TNBC）细胞。近 50% 的 TNBC 患者接受新辅助治疗（手术前）化疗（NACT；联合蒽环类药物、铂类药物和/或紫杉烷类药物）将产生大量残留肿瘤负担，导致极高的复发和死亡风险4。目前尚无获批的靶向治疗药物用于非 BRCA 突变 TNBC 的新辅助治疗。因此，迫切需要找到根除的方法残留的肿瘤细胞。此外，驱动化疗耐药 TNBC 代谢重编程的机制不清楚。我们对 NACT 前后患者来源的异种移植物 (PDX) 和人类 TNBC 进行连续比较活检显示残留肿瘤细胞中的 oxphos 特征增强，我们证明 oxphos 是一种残留 TNBC 的独特治疗脆弱性。我们观察到蛋白质水平显着升高 NACT 后与 NACT 前 TNBC 活检中线粒体融合驱动的 GTPase 视神经萎缩 1 (OPA1)。此外，乳腺癌中线粒体融合驱动蛋白的高表达与生存率低有关。这线粒体结构（由线粒体裂变和融合的平衡决定）对新陈代谢的影响不同肿瘤类型的差异很大。尽管线粒体对新陈代谢很重要，但尚无研究表明讨论了线粒体结构如何影响驱动 TNBC 治疗反应的代谢状态。我们的初步数据证明 NACT 可以增加体外和体内线粒体融合和代谢。我们可以通过遗传或药理学干扰来增加 TNBC 细胞中的 oxphos 和 NACT 耐药性使用 Drp1 抑制剂 Mdivi-1 进行线粒体裂变。相反，线粒体融合的扰动 MYLS22 是一种 OPA1 抑制剂，可降低 oxphos 和 NACT 耐药性。我们假设 OPA1 驱动线粒体融合介导 NACT 诱导的代谢转换，以促进 TNBC 细胞的化疗耐药性。为了解决这个问题，我们的具体目标是：1）确定线粒体融合是否与化疗有关 - 在 TNBC 中诱导 oxphos，以及 2) 在残余 TNBC 小鼠模型中定位并量化线粒体融合，以及连续患者活检。这些结果将增加我们对调控机制的理解线粒体生命，以及驱动 TNBC 代谢适应的机制。此外，我们的研究结果将提供额外的代谢治疗靶点来克服残留 TNBC 的化疗耐药性。