Esophageal adenocarcinoma (EAC) incidence rose dramatically over the last decades. Since genomic analyses did not reveal common targets for therapies, treatment options are limited and prognosis is poor. EAC patients show large differences in response to neoadjuvant treatment but no biomarkers are known that predict initial and long term response to therapy.
It has been demonstrated for some solid tumors that cancer associated fibroblasts (CAFs) play an important role in tumor biology and for metastases. To investigate whether functional changes in CAFs are responsible for differences in treatment response and early metastases, cell type-specific transcriptome analyses are needed. It is now possible to perform single cell transcriptomics but this approach is still not scalable to investigate enough samples for clinical association. We have developed a protocol that combines fluorescence activated cell sorting with RNA-seq, allowing to analyse the transcriptomes of leukocytes, epithelial cells and fibroblasts separately.
We will apply this concept to treatment naïve EAC biopsies and normal tissues and will systematically identify cell-type specific alterations that correspond to treatment response and relapse. We will validate our findings using a large collection of EAC tissues for targeted assays and by experiments in tissue culture. Overall, we will be able to identify functional changes in CAFs and other tumor components that will help to explain the clinical course of an EAC patient and that provide new opportunities for intervention.
A better understanding of the tumor microenvironment with its different cell types is needed to clarify their roles for treatment response and disease progression of EAC.
We will define the transcriptomic profiles of leukocytes, fibroblasts and epithelial cells of EAC and normal tissue and will identify critical pathways in CAFs that correlate with treatment response and metastases. We will use this information to derive opportunities for new treatment concepts.