H2020Индивидуална стипендия2018–2020

MDCRC · Metabolic Dynamics in Colorectal Cancer

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

Период: 2018-05-01 → 2020-07-19
Финансиране от ЕС: 180 277 €
Участници: 1
Схема: MSCA-IF-EF-RI

Линиите свързват координатора с партньорите.

Накратко на български

Метаболизмът на глюкозата в чревните стволови клетки се анализира, за да се разбере как те се превръщат в ракови. Това помага за по-доброто разбиране на механизмите, чрез които се развива и разпространява ракът на дебелото черво.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Metabolic Dynamics in Colorectal Cancer

Colorectal carcinoma (CRC) is the second most common cancer in Europe and the third most common cancer worldwide. Despite several genetic and transcriptomic studies have provided valuable information contributing to the improvement in the diagnosis and treatment of CRC, its outcome still remains poor, with a 5-year survival rate of 60% and approximately half of the patients dying of their disease despite curative resection. These poor treatment outcomes highlight the need to better understand the mechanisms that account for CRC initiation, progression and spreading. Colorectal tumors are highly heterogeneous and they are continuously maintained by a small population of cells with stem cell activity, the so-called cancer stem cells (CSCs). These tumor initiating cells or CSCs derive from stem cells present in the normal intestinal epithelium, named intestinal stem cells (ISCs). Therefore, elucidating the molecular mechanisms involved in the expansion of the ISC pool and regulating the acquisition and maintenance of tumor-initiating cells will provide us with a better understanding of how intestinal tumors originate and propagate, a key step for metastatic dissemination and tumor relapse. In this context, our previous work and preliminary data obtained before starting this project demonstrated a prominent role of glucose metabolism on CRC. Based on this, we sought to study the role of glucose metabolism on ISCs dynamics and its role in CRC initiation and progression. To explore this, I proposed two specific aims: 1. To analyze the role of metabolic reprogramming in ISCs and its contribution to CRC 2. To study the metabolic evolution of CRC. The completion of this project has revealed a novel subtype of ISC displaying a very active glucose metabolism. These cells have strong stem cell potential and can give rise to intestinal and colon tumors in a mouse model of colorectal cancer. Furthermore, we have found that these highly glycolytic cells are also present in human colorectal tumors and might be involved in tumor progression. These studies have provided a comprehensive picture of the role of metabolism on CRC tumorigenesis, which will potentially provide the rationale to target metabolism in CRC to improve current therapies and reduce CRC incidence and mortality.

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

Цел на проекта

Metabolic reprogramming has recently emerged as a key hallmark of cancer. Despite many efforts made to identify metabolic properties of cancer cells, there is a complete lack of understanding of the specific steps in the tumorigenic process when this metabolic rewiring occurs and its biological consequences. In this regard, our previous work has revealed a critical role of glucose metabolism in driving tumor initiation, in particular in the intestine. Importantly, recent studies have demonstrated that intestinal stem cells (ISCs) are the cell of origin of colorectal cancer (CRC), and our preliminary data suggests that glucose metabolism could be important for ISC activity. Based on these findings, we propose to study the specific metabolic properties of intestinal stem cells (ISCs) and its relevance in stem cell dynamics and CRC initiation and progression. Specifically, we will develop three aims:1. To analyze the role of metabolic reprogramming in ISCs and its contribution to CRC by employing a combination of genetic, metabolic and imaging techniques.2. To study the metabolic evolution of CRC. In this aim, by using patient-derived xenografts and intestinal organoids expressing a genetically encoded metabolic reporter, we will analyze glucose metabolism in vivo at a single cell level to define step-wise the role of metabolic reprogramming in CRC progression. All together, the successful completion of this proposal will identify the specific cells and steps during CRC where glucose metabolism is functionally relevant and the underlying molecular mechanisms, thus expanding our view of metabolic reprogramming beyond the idea of being just an adaptation to increased proliferation. Importantly, the results derived from this project could potentially be used to improve current therapies by targeting specific metabolic pathways.

Оригинален текст от CORDIS (на английски).

Участници

ISTITUTO NAZIONALE ONCOLOGICO CANDIOLO · CANDIOLOКоординаторИталия