H2020Индивидуална стипендия2019–2021

INHuMAN · Intra-tumoral heterogeneity in NRAS-driven metastatic melanoma

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

Период: 2019-04-01 → 2021-03-31
Финансиране от ЕС: 166 320 €
Участници: 1
Схема: MSCA-IF-EF-ST

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Накратко на български

Разнообразието на клетките при метастатичен меланом се анализира чрез търсене на специфични групи, които задвижват разпространението на рака. Разбирането на тези механизми помага за разработването на по-ефективни терапии и по-точна диагностика за пациентите.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Intra-tumoral heterogeneity in NRAS-driven metastatic melanoma

Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. An incomplete view of the mechanisms that drive metastasis has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for patients. The mechanisms contributing to metastatic dissemination can be diverse and tumor-type dependent. Skin cancers are prime examples of this. Whereas skin basal cell carcinoma rarely metastasize, cutaneous melanoma are often highly metastatic. Intra-tumor heterogeneity (ITH) has been proposed as a major driver of metastatic dissemination where the magnitude of heterogeneity has not been fully addressed yet. In the action “INHuMAN” we proposed to address the magnitude of intratumoral heterogeneity in melanoma and identify cell populations at the origin of metastasis. Combining single cell RNA sequencing with clinically relevant mouse models we were able to identify and characterize a cell state that presumably sits at the origin of metastasis. Importantly, the data strongly suggested that this population is not fueling tumor growth. Our initial screening assays identified a melanoma population with stemness characteristics indicating that these cells maintain melanoma growth. We developed models and tools to further study this population and by following the fate of individual cells and their spatial distribution in the tissue we identified a specialized cellular niche, called perivascular niche, that maintains tumor growth and is not linked to metastasis. Instead, the metastatic population was driven by a Transcription Factor called PRRX1, where these Metastatic Initiating Cells (MICs) where preferentially at the invading front of primary melanoma tumors. Importantly, the existence and the spatial location of the two cell states were confirmed in human biopsies. In this call we have characterized this cellular plasticity and based on this data we have initiated projects to better characterize when and how cells transit, in order to block this phenotypic switch. The outcome of this fundamental action can be subjected to translational research that potentially can lead to the development of treatment strategies (personalized or not) to eradicate this devastating disease and improve patient’s survival.

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

Цел на проекта

Metastasis is largely refractory to therapy and, thereby, responsible for 90% of cancer-related deaths. An incomplete view of the mechanisms that drive metastasis has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for metastatic patients. There is increasing evidence that this multi-step process involves reversible non-genetic reprogramming events allowing cancer cells to acquire diverse phenotypic features needed to migrate, invade, intra/extra-vasate and actively adapt to the varying environment (stress) they encounter. Understanding metastasis therefore requires methodologies that capture the magnitude and dynamics of non-genetic reprogramming in 4D (space and time) at the single-cell resolution. The advent of reliable single-cell multi-Omics analytical tools allows the simultaneous profiling of single cell’s genome, epigenome and transcriptome. Integrating single-cell profiling with lineage tracing provides a robust framework for defining cell fate transitions, intermediate states and trajectory inference. The host lab has recently used such a powerful combination of approaches to study the cellular origin of melanoma, the early molecular events associated with initiation of the disease and to portray cell state dynamics during therapy response. I propose to exploit this know-how to perform a longitudinal and exhaustive analysis of the diversity and trajectories of melanoma cell states during metastatic dissemination using a clinically-relevant mouse model of melanoma, a disease with a very high metastatic propensity. The gene regulatory networks underlying the identified metastatic cell states will be deciphered and the data exploited to develop therapeutic modalities targeting (amenable) drivers of state switching that contribute to early key steps of the metastatic process. The project is expected to lead to new avenues for early detection and interception of metastatic melanoma.

Оригинален текст от CORDIS (на английски).

Участници

VIB VZW · ZWIJNAARDE - GENTКоординаторБелгия