Dissecting the impact of epithelial stem cell niches on oral cancer heterogeneity

Información del proyecto

OralNiche

Identificador del acuerdo de subvención: 101042738

DOI

10.3030/101042738

Fecha de la firma de la CE 24 Marzo 2022

Fecha de inicio 1 Junio 2022

Fecha de finalización 31 Mayo 2027

Financiado con arreglo a

• European Research Council (ERC)

Coste total

€ 1 768 583,00

Aportación de la UE

€ 1 768 583,00

Coordinado por

JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Germany

Periodic Reporting for period 1 - OralNiche (Dissecting the impact of epithelial stem cell niches on oral cancer heterogeneity)

Período documentado: 2022-06-01 hasta 2024-11-30

Resumen del contexto y de los objetivos generales del proyecto

Oral cancer or oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancer. OSCC is a particularly heterogeneous cancer with a high risk of metastasis. Despite medical advances, the overall survival of OSCC patients has improved very little. Response to treatment remains highly variable from patient to patient. One in two patients dies from the disease. OSCC is not evenly distributed among oral sites, suggesting a possible cell biological basis for the heterogeneity of this cancer.

OSCC arises from the oral epithelium, which is a unique tissue. Each of its different sites, such as the tongue, cheeks, gums and palate, has different functions and a high degree of structural heterogeneity. Without these specialised oral sites, eating, tasting and speaking would not be possible. Each oral site is unique and contains distinct cellular microenvironments, or 'niches', for oral epithelial stem cells. Despite their importance, our understanding of oral stem cell niches remains limited.

The OralNiche project aims to fill this knowledge gap by systematically investigating oral stem cell niches and determining whether these niches contribute to the heterogeneity seen in oral cancer. To achieve this, we will first locate stem cells in different oral sites, identify all cell types in the vicinity of oral stem cells and generate a map of their localisation within oral stem cell niches. We will then define how niche cells influence stem cells and how stem cell niches are altered during oral cancer development. Based on these findings, we aim to eventually identify novel biomarkers and potential new therapeutic targets to improve the diagnosis and treatment of oral cancer.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

In the course of the OralNiche project, we identified a new candidate marker of oral stem cells, which we are now validating in the in vitro and in vivo settings. We have further established a map of the cells within the stem cell niches using single-cell and spatial transcriptomics and identified different molecules that may regulate the function of oral stem cells. These signalling molecules are secreted by specialised stromal cells in the vicinity of oral stem cells called fibroblasts. From these identified signalling molecules, we are now testing their role in regulating oral stem cells in a healthy state. We will follow this up by mapping on the single-cell level how the stem cells and their niches are transformed in response to cancer formation as well as treatment with chemotherapy.

In addition to these efforts, we have successfully started to establish a biobank of organoids derived from tissue samples of oral cancer patients. We now have cancer organoid lines (n = 18) derived from primary tumours arising from the alveolar process, gingiva, palate and tongue, as well as metastatic tumours from the lymph nodes. These tumour organoids are mini-versions of the patient's cancer, and we will use them to validate new biomarkers and therapeutic targets identified in the OralNiche project. We have built a drug screening platform that allows us to print the organoids in multi-well plates, expose them to different chemotherapies and assess whether the organoids respond to treatment.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

To date, the OralNiche project has achieved several major goals that have significantly advanced our understanding of the oral epithelium and its stem cell niches. We have surveyed different oral sites, including the palate, cheeks and tongue, to build a comprehensive atlas of the cell types found in the stem cell niches of each oral site. Using this atlas, we constructed a network of cell-cell interactions showing which cell types communicate with the stem cells. Our analysis identified several signalling molecules secreted by specialised niche cells called fibroblasts that control stem cell function. We then created miniature versions of the oral epithelium, called organoids, and tested how these signalling molecules affected the oral stem cells. Our data show for the first time that stem cells from different oral sites respond differently to the signalling molecules, highlighting how structural and cellular heterogeneity between oral sites can be controlled. We have complemented the single-cell atlas with a spatial transcriptomics dataset that serves as a map of the location of individual cell types within the oral mucosal tissues. The datasets provide valuable resources for the scientific community to explore cells of interest and their interaction with other cell types.

In the second part of the OralNiche project, we are using established tools to understand the transformation of the stem cell niche during oral cancer and anti-cancer cancer chemotherapy. We aim to unravel the intrinsic changes within the cancer cells as well as the extrinsic changes within the cancer cell microenvironment. We will use single-cell and spatial transcriptomics, organoids and in vivo experiments. We will use compound screens and gene editing technology to validate newly identified mechanisms.

We will further translate our findings into the clinical setting using patient-derived organoids, which we are currently establishing in collaboration with our clinical partners. Our ultimate goal is to use the knowledge gained from the OralNiche project to better understand oral mucosal biology and improve oral cancer diagnosis and treatment.