Elucidating the role and regulation of periostin in therapy-induced chemoresistance in metastatic breast cancer

阐明骨膜素在转移性乳腺癌化疗耐药中的作用和调节

基本信息

批准号：
10408263
负责人：
Daniel Patrick Regan
金额：
$ 10.3万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408263
关键词：
3-Dimensional Adherent Culture Automobile Driving BT 474 Bioinformatics Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy Cancer Cell Growth Cell Culture Techniques Cell Proliferation Cell Survival Cells Cessation of life Chemoresistance Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Cultured Cells Data Disease Disease remission Distant Distant Metastasis Drug resistance Essential Genes Female Fibroblasts Funding Future Gene Targeting Genes Grant Guide RNA Human In Vitro Investigation K-Series Research Career Programs Knowledge Laboratories Libraries Link Lung Malignant Neoplasms Mediating Mentored Research Scientist Development Award Metastatic breast cancer Modeling Neoplasm Metastasis Non-Malignant Parents Pathway Analysis Pharmaceutical Preparations Phenotype Primary Neoplasm Process Proteins Recurrence Regulation Resistance Role Signal Pathway Site Stromal Cells Systemic Therapy T47D Testing United States Woman Work base breast cancer survival cancer cell cancer therapy cell type chemotherapy experimental study genome wide screen genome-wide hormone receptor-positive in vitro Model in vivo lung metastatic malignant breast neoplasm molecular subtypes mortality neoplastic cell new therapeutic target novel periostin response triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

Project Summary Approximately 450,000 women succumb to breast cancer each year, making it the most common cause of female cancer mortality globally, with the majority of these deaths resulting from metastatic disease. In the treatment of metastases, the initial drug response rate is only about 50%, as compared to 90% observed in the treatment of primary tumors. Furthermore, resistance to these systemic therapies typically develops more quickly in the metastatic setting. While numerous studies have focused on tumor cell intrinsic mechanisms of metastasis and drug resistance, there have been very few investigations into how non- malignant host cells of the metastatic tumor microenvironment extrinsically promote these processes. Fibroblasts are one cell type present in the tumor microenvironment which have been linked to several tumor growth and metastasis promoting activities. Despite this emerging paradigm, very few studies have evaluated the contributions of lung fibroblasts to extrinsic mechanisms of cancer cell survival and chemo-resistance, a reflection of the difficulty of conducting these investigations in vivo, and the paucity of in vitro models which reliably recapitulate in vivo tumor-stroma interactions. Our laboratory has fully optimized a 3D lung-like organotypic co-culture model which effectively incorporates both tumor cells and primary resident stromal cells from secondary sites of metastasis. Utilizing this model, our preliminary data demonstrate that lung fibroblasts modulate significant phenotypic differences in human breast cancer cell proliferation and drug response, in a breast cancer molecular-subtype dependent manner. Based on these data, we hypothesize that we can identify tumor cell specific genes whose function is essential for their attainment of pro-survival and drug resistant phenotypes upon interaction with lung fibroblasts. To investigate this, we propose to conduct a genome-wide CRISPR “stromal synthetic lethal” screen against human breast cancer cells cultured in the presence or absence of primary human lung fibroblasts. Results of these studies will fill a critical knowledge gap regarding lung fibroblast mediated promotion of breast cancer survival and will uncover novel genes whose function/proteins can be targeted for assessment as potential novel anti-metastatic therapies for breast cancer.

项目摘要每年大约有450,000名妇女屈服于乳腺癌，使其成为最常见的全球女性癌症死亡率的原因，大多数这些死亡是由转移性疾病引起的。在转移的治疗中，初始药物缓解率仅约50％，而观察到的90％在原发性肿瘤的治疗中。此外，对这些全身疗法的耐药性通常会发展在转移环境中更快。虽然大量研究集中于肿瘤细胞的固有转移和耐药性的机制，很少有人研究非 - 转移性肿瘤微环境的恶性宿主细胞外在促进这些过程。成纤维细胞是肿瘤微环境中存在的一种细胞类型，与几个肿瘤有关增长和转移促进活动。尽管有这些新兴范式，但很少有研究评估肺成纤维细胞对癌细胞存活和化学抗性外部机制的贡献，一种反映了在体内进行这些研究的困难以及体外模型的稀少可靠地概括了体内肿瘤 - 基质相互作用。我们的实验室已经完全优化了3D肺样有效地结合了肿瘤细胞和主要居民基质细胞的有机共培养模型来自转移的次要部位。利用此模型，我们的初步数据证明了肺成纤维细胞调节人类乳腺癌细胞增殖和药物反应的显着表型差异。乳腺癌分子 - 补充依赖性方式。基于这些数据，我们假设我们可以识别肿瘤细胞特异性基因，其功能对于获得促生存和药物至关重要与肺成纤维细胞相互作用后的抗性表型。为了调查这一点，我们建议进行全基因组CRISPR“基质合成致死”筛查，针对人类乳腺癌细胞培养的人类乳腺癌细胞原发性人肺成纤维细胞的存在或不存在。这些研究的结果将填补关键知识关于肺成纤维细胞介导的促进乳腺癌生存的差距，并将发现新的基因可以将其功能/蛋白质作为对乳房的潜在抗反转移疗法的评估的目标癌症。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rotator cuff repair using a bioresorbable nanofiber interposition scaffold: a biomechanical and histologic analysis in sheep.

DOI：
10.1016/j.jse.2021.07.018
发表时间：
2022-03
期刊：
JOURNAL OF SHOULDER AND ELBOW SURGERY
影响因子：
3
作者：
Romeo, Anthony;Easley, Jeremiah;Regan, Dan;Hackett, Eileen;Johnson, James;Johnson, Jed;Puttlitz, Christian;McGilvray, Kirk
通讯作者：
McGilvray, Kirk

Canine tonsillar neoplasia and tonsillar metastasis from various primary neoplasms.

DOI：
10.1111/vco.12604
发表时间：
2020-12
期刊：
Veterinary and comparative oncology
影响因子：
2.1
作者：
Mickelson MA;Regan D;Randall EK;Worley D;Seguin B
通讯作者：
Seguin B

Immunization against full-length protein and peptides from the Lutzomyia longipalpis sand fly salivary component maxadilan protects against Leishmania major infection in a murine model.

DOI：
10.1016/j.vaccine.2017.10.039
发表时间：
2017-12-04
期刊：
Vaccine
影响因子：
5.5
作者：
Wheat WH;Arthun EN;Spencer JS;Regan DP;Titus RG;Dow SW
通讯作者：
Dow SW

Evaluation of lumbar spinal fusion utilizing recombinant human platelet derived growth factor-B chain homodimer (rhPDGF-BB) combined with a bovine collagen/β-tricalcium phosphate (β-TCP) matrix in an ovine model.

DOI：
10.1002/jsp2.1166
发表时间：
2021-09
期刊：
JOR spine
影响因子：
3.7
作者：
Gadomski BC;Labus KM;Puttlitz CM;McGilvray KC;Regan DP;Nelson B;Seim HB 3rd;Easley JT
通讯作者：
Easley JT

Bony ingrowth potential of 3D-printed porous titanium alloy: a direct comparison of interbody cage materials in an in vivo ovine lumbar fusion model.