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HIF-1α in Cancer-Associated Fibroblasts: Unveiling implications for the tumor microenvironment and therapeutic strategies

Project description

Uncovering a hidden driver of colorectal cancer

Colorectal cancer (CRC) is one of the deadliest cancers worldwide, with many patients facing poor outcomes due to metastasis. Cancer progression is strongly influenced by cancer-associated fibroblasts (CAFs), which alter the tumour’s environment to support growth and evade the immune system. Hypoxia, or low oxygen levels, is common in advanced tumours and activates HIF-1α, a protein that helps cancer cells survive harsh conditions. While much is known about HIF-1α in cancer cells, its role in CAFs remains unclear. Supported by the Marie Skłodowska-Curie Actions programme, the HifCAT project explores how HIF-1α affects CAFs in CRC. The aim is to uncover how CAFs drive tumour progression and metastasis, ultimately paving the way for better treatments.

Objective

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Despite significant advancements in understanding CRC pathogenesis, the clinical prognosis of CRC patients is still poor due to metastasis dissemination. Cancer progression is often associated with the presence of cancer-associated fibroblasts (CAFs) in the tumor microenvironment that regulate processes such as extracellular matrix (ECM) deposition and repression of the immune response. The establishment of a hypoxic environment and activation of its main effector, the hypoxia-inducible factor-1α (HIF-1α), are common features of advanced cancers. HIF-1α is a transcription factor, which regulates several genes that are exploited by tumor cells to escape from a nutrient-deprived environment and to survive as well as resist to treatment. However, the role of HIF-1α in CAFs has not be addressed so far in CRC. This research seeks to elucidate the effects of hypoxia on different aspects of CAFs' function , using in vitro functional assays and innovative co-culture models with patient-derived CAFs and matching tumor organoids. Furthermore, the study aims to unveil the role of HIF-1α expression in CAFs during tumor initiation and progression using a colitis-associated carcinogenesis model and pinpoint the origin of HIF-1α+ CAFs employing a lineage tracing model. Finally, in silico analysis of scRNAseq data will allow to detect the subset of CAFs that are responsive to hypoxia in different stages of carcinogenesis and in metastatic dissemination. Overall, this project will study the unappreciated role of HIF-1α in CAFs in the context of CRC with the ultimate goal to pave the way to new therapeutic strategies.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2023-PF-01

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Coordinator

UNIVERSITE DU LUXEMBOURG
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 175 920,00
Address
2 PLACE DE L'UNIVERSITE
4365 ESCH-SUR-ALZETTE
Luxembourg

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Region
Luxembourg Luxembourg Luxembourg
Activity type
Higher or Secondary Education Establishments
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Total cost

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