H2020Индивидуална стипендия2016–2018

MRCKa in cancer · Targeting Cancer Cell Invasion and Metastasis by Inhibition of the Serine Kinase MRCKa

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2016-08-08 → 2018-08-07
Финансиране от ЕС: 200 195 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Протеинът MRCKa се изследва чрез генетично модифицирани мишки, за да се разбере как влияе върху разпространението на рака на гърдата. Това е важно, защото спирането на метастазите може да подобри прогнозата за пациентите с ракови заболявания.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Targeting Cancer Cell Invasion and Metastasis by Inhibition of the Serine Kinase MRCKa

Context Metastatic diseases are the primary reason for cancer death and metastatic spread drastically worsens the prognosis of cancer patients. Inhibiting metastatic spreading would therefore have the highest benefit. Paradoxically, anti-cancer therapeutics mainly focused on targeting the primary tumor, and little has been accomplished in terms of the development of anti-metastatic drugs. MRCKa is a Rho GTPase effector suggested to play an important role in cancer cell migration. Importantly, MRCKa is found to be overexpressed in many solid human cancers and has been identified in a gene expression profile of breast cancers with poor prognosis and high risk of metastasis. Although these data indicate that inhibition of MRCKa could be a promising strategy to inhibit metastasis, its molecular mechanisms of action and role in metastasis in vivo have not been established. Objectives In this study, I explored the potential of MRCKa as a therapeutic target for metastatic diseases using state-of-the-art genome editing and the first MRCKa knockout mice. The overall objectives were to: 1. Test for breast cancer development and metastasis in MRCKa knockout mice 2. Elucidate the molecular mechanisms of how MRCKa promotes migration 3. Explore the efficiencies of combinatorial knockout of MRCKa and its related kinases Conclusions 1. We generated and characterized the first MRCKa ko mice. Our data suggests that MRCKa may have a critical role in embryogenesis, as 50% of the knockout mice died during embryonic development. 2. We validated the role of MRCKa in cancer in vivo. Our data suggests that inhibition of MRCKa alone is not sufficient to inhibit breast cancer metastasis and tumor growth. 3. Our data also indicate a complex crosstalk between MRCKa and MRCKb in mediating cancer cell migration in vitro, as well as the different contribution of MRCK and ROCK signalling according to cancer subtype.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Metastasis is the primary reason for cancer death, and metastatic spread drastically worsens the prognosis of cancer patients. As cell migration is the biological process underlying the spread of cancer cells, better understanding of it is crucial for the development of novel therapies in reducing cancer invasion and increasing patient survival. Yet, little has been accomplished in terms of the development of anti-metastasis drugs. MRCKa is an effector of Rho GTPase, and molecular studies have suggested it to play important roles in cancer cell migration. However, the potential of targeting MRCKa in metastasis has not been validated due to the lack of in vivo evidence and specific inhibitors. Hence, this project aims to validate MRCKa as an important drug target for the treatment of metastatic cancers. The first objective aims to investigate the role of MRCKa in cancer development and metastasis by utilizing a breast cancer model on MRCKa knockout mice. Secondly, MRCKa was reported to influence cell migration by multiple mechanisms, including promoting cell contraction, reducing actin turnover, and filopodia formation. To better define the molecular signaling of MRCKa during metastasis, the importance of these effector pathways in cancer cell migration will be investigated. Specifically, MRCKa knockout breast cancer cell line derivatives will first be generated, and their ability to migrate and invade studied in 3D spheroid cultures. The importance of the effector pathways will be investigated through targeted gene inactivation and inhibitors. Finally,MRCKa has two closely related family members, MRCKb and MRCKg, and also shares functional similarities with ROCK1 and ROCK2. With the aim to obtain a more efficient inhibition of cancer cell migration, the third objective seeks to investigate the overlapping functions of related kinases through combining knockouts of MRCKa in breast cancer cells with knockouts of MRCKb, MRCKg, ROCK1 and ROCK2.

Оригинален текст от CORDIS (на английски).

Участници

KOBENHAVNS UNIVERSITET · KOBENHAVNКоординаторДания