Integrin-mediated mechanisms of prostate cancer progression

整合素介导的前列腺癌进展机制

• 批准号: 10524161
• 负责人: Lucia R. Languino
• 金额: $ 0.49万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524161
• 关键词: Adhesions; Affect; Androgen Receptor; Cancer Patient; Castration; Cell Communication; Cell surface; Cells; Chemicals; Data; Down-Regulation; Experimental Designs; Family; Focal Adhesions; In Vitro; Infiltration; Injections; Integrin alphaV; Integrin alphaVbeta3; Integrins; Investigation; Label; Ligands; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic to; Mus; Myeloid-derived suppressor cells; Normal Cell; Normal tissue morphology; Pathway interactions; Phenotype; Property; Prostate Cancer therapy; Proteomics; Receptor Activation; Regulation; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Surface; Technology; Testing; Therapeutic; Time; Up-Regulation; Variant; Western Blotting; antitumor effect; base; cancer cell; cancer type; castration resistant prostate cancer; exosome; experimental study; in vivo; in vivo Model; innovation; insight; monocyte; mouse model; multidisciplinary; new therapeutic target; prevent; prostate cancer cell; prostate cancer model; prostate cancer prevention; prostate cancer progression; receptor; response; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression; uptake

ABSTRACT Therapeutic approaches aimed at curing prostate cancer (PrCa) are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to chemical castration of PrCa patients. Recently, we have, for the first time, described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for PrCa treatment; this molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We have demonstrated unique properties of this molecule in PrCa that are not observed for other integrins: we have shown that αvβ6 promotes castrate- resistant prostate cancer (CRPC) via activation of JNK and androgen receptor (AR). Furthermore, we have shown that αvβ6 is found in cancer cell exosomes, is transferred from cancer cells to recipient cells by exosomes and remains active in the recipient cells. We also demonstrate that αvβ6 has profound effects on the microenvironment. Specifically, αvβ6 prevents induction of the Stat1/Mx1/2 signaling pathway in donor cancer cells, and their exosomes, and its down-regulation in cancer cell exosomes inhibits monocyte M2 polarization. Finally, we demonstrate that αvβ6 inhibition in vivo causes upregulation of the Stat1/MxA/B signaling pathway in cancer cells. Based on our highly rigorous mechanistic studies, we propose the following innovative hypothesis: αvβ6 expression affects the microenvironment by down-regulating Stat1/Mx1 levels in donor cells, and subsequently in cancer cell exosomes and recipient cells, thereby promoting monocyte differentiation, tumor growth, and cancer progression. Consequently, by down-regulating or inhibiting αvβ6 in cancer cells, increased Stat1/MxA/B levels in cells/ exosomes/ monocytes will be generated producing an anti-tumor effect. To test this hypothesis, we plan the following three specific aims. We will examine in vitro the role of αvβ6 integrin in regulating cancer cell - monocyte crosstalk (Aim 1), and analyze in vivo the functional role of the pathway mediated by exosomal αvβ6 and/or Stat1 in cancer progression (Aim 2) and characterize the αvβ6 integrin/Stat1 pathway in PrCa cells (Aim 3). Innovative approaches, highly purified exosomes and in vivo models will be used to test our hypothesis that transfer of integrins and their downstream effectors from cancer cells to other cells in the tumor microenvironment promotes CRPC. The study will be supported by a multidisciplinary team of investigators who have extensive and complementary expertise in all the required technologies. Based on our preliminary data on the αvβ6/Stat1 pathway and planned experimental design for this project, we expect that our study will elucidate new mechanisms that promote PrCa and validate new targets for PrCa therapeutic approaches.

抽象的 鉴于以下因素，旨在治愈前列腺癌 (PrCa) 的治疗方法仅取得部分成功 化学阉割经常导致高度转移抗性表型的出现 最近，我们首次描述了整合素家族的表面受体αvβ6。 作为 PrCa 治疗的新型治疗靶点；该分子是一个理想的靶点，因为与其他整合素不同，它 存在于不同类型的癌症中，但不存在于正常组织中，我们已经证明了其独特的特性。 PrCa 中的分子在其他整合素中未观察到：我们已经证明 αvβ6 促进去势- 通过激活 JNK 和雄激素受体 (AR) 来治疗耐药性前列腺癌 (CRPC)。 研究表明，αvβ6 存在于癌细胞外泌体中，通过以下方式从癌细胞转移到受体细胞： 我们还证明 αvβ6 对外泌体具有深远的影响。 具体来说，αvβ6 可以阻止供体中 Stat1/Mx1/2 信号通路的诱导。 癌细胞及其外泌体，其在癌细胞外泌体中的下调抑制单核细胞 M2 最后，我们证明体内 αvβ6 抑制会导致 Stat1/MxA/B 上调。 癌细胞中的信号通路。 基于我们高度严格的机械研究，我们提出以下创新假设：αvβ6 表达通过下调供体细胞中 Stat1/Mx1 水平来影响微环境，随后 在癌细胞外泌体和受体细胞中，从而促进单核细胞分化、肿瘤生长和 通过下调或抑制癌细胞中的αvβ6，研究发现癌症进展增加。 细胞/外泌体/单核细胞中的 Stat1/MxA/B 水平将产生，从而产生抗肿瘤效果。 根据这一假设，我们计划以下三个具体目标：我们将在体外研究αvβ6整合素的作用。 调节癌细胞-单核细胞串扰（目标1），并分析该通路的体内功能作用 外泌体 αvβ6 和/或 Stat1 在癌症进展中介导（目标 2）并表征 αvβ6 PrCa 细胞中的整合素/Stat1 通路（目标 3）。 创新方法、高度纯化的外泌体和体内模型将用于检验我们的假设： 整合素及其下游效应子从癌细胞转移到肿瘤中的其他细胞 微环境促进 CRPC 的研究将得到多学科研究团队的支持。 根据我们的初步调查，他们在所有所需技术方面拥有广泛且互补的专业知识。 关于 αvβ6/Stat1 途径的数据和该项目计划的实验设计，我们预计我们的研究将 阐明促进 PrCa 的新机制并验证 PrCa 治疗方法的新靶点。

项目成果

STEAP1-4 (Six-Transmembrane Epithelial Antigen of the Prostate 1-4) and Their Clinical Implications for Prostate Cancer.

STEAP1-4（前列腺六次跨膜上皮抗原 1-4）及其对前列腺癌的临床意义。

• 发表时间: 2022-08-20
• 影响因子: 5.2
• 作者: Xu, Michael;Evans, Latese;Bizzaro, Candice L;Quaglia, Fabio;Verrillo, Cecilia E;Li, Li;Stieglmaier, Julia;Schiewer, Matthew J;Languino, Lucia R;Kelly, William K
• 通讯作者: Kelly, William K

IFIT3 (interferon induced protein with tetratricopeptide repeats 3) modulates STAT1 expression in small extracellular vesicles.

IFIT3（具有四肽重复序列 3 的干扰素诱导蛋白）调节小细胞外囊泡中的 STAT1 表达。

• 发表时间: 2021
• 作者: Naranjo, Nicole M;Salem, Israa;Harris, Maisha A;Languino, Lucia R
• 通讯作者: Languino, Lucia R

Activated Extracellular Vesicles as New Therapeutic Targets?

活化的细胞外囊泡作为新的治疗靶点？

• 发表时间: 2019
• 影响因子: 19
• 作者: Languino, Lucia R;Hooper, D Craig
• 通讯作者: Hooper, D Craig

Announcing the ISEV2020 special achievement award recipients: Andrew Hill and Edit Buzás; and the recipient of the ISEV2020 special education award: Carolina Soekmadji.

宣布 ISEV2020 特别成就奖获得者：Andrew Hill 和 Edit Buzás；

• 发表时间: 2020-10
• 作者: Witwer, Kenneth W;Languino, Lucia R;Weaver, Alissa M;Wauben, Marca H
• 通讯作者: Wauben, Marca H

Tumor-Derived Extracellular Vesicles Require β1 Integrins to Promote Anchorage-Independent Growth.

肿瘤来源的细胞外囊泡需要 β1 整合素来促进锚定非依赖性生长。

• 发表时间: 2019-04-26
• 影响因子: 5.8
• 作者: DeRita, Rachel M;Sayeed, Aejaz;Garcia, Vaughn;Krishn, Shiv Ram;Shields, Christopher D;Sarker, Srawasti;Friedman, Andrea;McCue, Peter;Molugu, Sudheer Kumar;Rodeck, Ulrich;Dicker, Adam P;Languino, Lucia R
• 通讯作者: Languino, Lucia R