Project title: Deciphering clonal evolution and tumor microenvironment in patients with DIPNECH

Description

What critical problem/question will researchers try to answer?
Despite the increased detection of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, DIPNECH, in clinical settings over the past decade, there remains limited information on the genetic background and pathophysiology of this condition. This project aims to elucidate the oncogenesis of DIPNECH and explore its genetic underpinnings.

Why is this important?
DIPNECH is a poorly understood neuroendocrine lung disease, with limited knowledge about its onset and progression. Its nonspecific symptoms often lead to misdiagnosis, such as refractory asthma. Our research aims to improve understanding of the mechanisms driving this condition, potentially paving the way for novel therapeutic approaches.

What will the researchers do?
We have access to a rare cohort of well-characterized DIPNECH patients who have undergone lung cancer resections, with associated tissue samples, including blocks and snap-frozen specimens representing the full spectrum of lesions linked to this disease. We will perform comprehensive profiling of these lesions using cutting-edge spatial phenotyping techniques for tumor microenvironment (TME) characterization, such as high-plex immunophenotyping and spatial transcriptomics. Additionally, we will use advanced bioinformatics methods, developed by co-PI Dr. D. Weghorn, to analyze the evolution and genomic characteristics of DIPNECH lesions. Finally, we will apply ATAC-sequencing to identify chromatin accessibility and factors influencing gene expression that are not detectable with conventional sequencing methods.

How might this improve treatment of neuroendocrine cancer?
This project addresses a critical clinical gap by characterizing the molecular profile of DIPNECH in a well-defined patient population. Our findings will enhance understanding of the disease’s initiation and progression, potentially leading to improved diagnostic sensitivity and accuracy. By mapping the clonal evolution of neoplastic cells across DIPNECH lesions, we hope to identify key molecular drivers of the condition. Ultimately, this research could uncover molecular targets, making this subset of lung tumors amenable to personalized therapeutic strategies.

What is the next step?
Following this study, we aim to develop an animal model of DIPNECH that replicates key clinical features of the disease. This model will allow us to further dissect the molecular mechanisms driving DIPNECH and identify actionable targets for therapeutic development.

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