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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.

项目概要每年约有 450,000 名女性死于乳腺癌，使其成为最常见的癌症是全球女性癌症死亡的原因，其中大部分死亡是由转移性疾病造成的。在转移瘤的治疗中，初始药物反应率仅为 50% 左右，而观察到的药物反应率为 90% 在原发性肿瘤的治疗中。此外，通常会对这些全身疗法产生耐药性在转移环境中更快。虽然许多研究都集中在肿瘤细胞内在转移和耐药机制，但很少有人研究非转移性肿瘤微环境的恶性宿主细胞从外部促进这些过程。成纤维细胞是肿瘤微环境中存在的一种细胞类型，与多种肿瘤有关生长和转移促进活动。尽管存在这种新兴范式，但很少有研究评估肺成纤维细胞对癌细胞存活和化疗耐药的外在机制的贡献反映出在体内进行这些研究的难度以及体外模型的缺乏可靠地重现体内肿瘤-基质相互作用。我们的实验室已经全面优化了3D类肺器官型共培养模型，有效整合肿瘤细胞和原代基质细胞来自继发性转移部位。利用该模型，我们的初步数据表明肺成纤维细胞调节人乳腺癌细胞增殖和药物反应的显着表型差异乳腺癌分子亚型依赖方式。根据这些数据，我们假设我们可以识别肿瘤细胞特异性基因，其功能对于实现促生存和药物至关重要与肺成纤维细胞相互作用后产生耐药表型。为了调查这一点，我们建议进行一次针对在培养皿中培养的人类乳腺癌细胞进行全基因组 CRISPR“基质合成致死”筛选存在或不存在原代人肺成纤维细胞。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乳腺癌生存促进的差距并将发现新的基因其功能/蛋白质可以作为潜在的新型乳腺抗转移疗法进行评估癌症。

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.