Deciphering the chemotherapy resistance of esophageal squamous carcinoma.

Supervisor: Dr. Benjamin Beck

Cancer remains the second main cause of deaths worldwide. Among this ensemble of diseases, esophageal cancer (EC) is the eight most frequent cancer globally and ranks as the sixth deadliest cancer worldwide. It is a significant health problem that accounts for approximately 450,000 new cancer cases annually worldwide. Patients diagnosed with EC show a high mortality rate with a 5-year survival ranging between 10 to 25%. Unlike other cancers, the outcome of EC has remained unchanged during the past decades mainly due to the poor response of EC tumors to the first line of treatment, especially in the case of locally advanced tumors. First-line treatment mainly consists of surgery with an adjuvant genotoxic treatment combined or not with mitotic poisons. However, this has shown poor efficacy as such treated patients developed recurrences, causing death in a year.  A deep understanding of the pathogenesis is required to improve the treatment offered to patients with EC. Genomics analyses have pictured over the years a broad heterogenic genetic landscape between individuals with EC as well as inter- and intra-tumors, hampering in fine the approval of alternative treatments against EC.

The research in our laboratory is focused to further understand the pathology of esophageal cancers. Esophageal cancer comprises two distinct diseases: squamous cell carcinoma (eSCC) and adenocarcinoma (eAC). Although both share the same anatomical site, they differ histologically, pathologically and epidemiologically. eSCC accounts for 90% of esophageal cancer cases worldwide. It develops via a multistep process originating from the squamous epithelial cells forming the inner lining of the esophagus. eSCC arises from basal cell hyperplasia and progresses gradually to low-grade (LGIEN), high-grade (HGIEN) intraepithelial neoplasia and ultimately to invasive carcinoma and metastases. Smoking and alcohol consumption are the two strongest established risk factors on the development of eSCC and present synergistic effects.  Unfortunately, despite improvements in the survival of patients treated with radiochemotherapy, the mortality rate of patient with eSCC barely improved in years.

To reduce the mortality rate associated with these cancers, it is crucial to better understand the origin of esophageal cancers and the molecular mechanisms underlying the development of these diseases and translate that knowledge into novel approaches for their diagnosis, prognosis and/or treatment. This led our lab to investigate the molecular core in eSCC and identify factors that affect the response of eSCC tumors to first line treatment. At this end, our group takes advantage of a multi-system approach combining in vitro analysis, in vivo murine models of eSCC to translate the findings in the near future in clinics. The proposed project will consist to assess and decipher the response of eSCC to first line treatment, play with their response and assess the interplay with various mechanisms such as the cell cycle, the DNA damage response, the circadian cycle and metabolism. For this, a broad range of techniques will be used including state-of-the-art multi-omics analyses (transcriptomics RNA-seq, ATAC-seq, (phospho)proteomic by MS, CHROMASS) and validate those understandings/findings in vivo. Insights into such chemotherapy response or resistance from eSCC will lead to the identification of markers that could guide clinicians to the choice of effective treatment for each patient.

Techniques:

  • Genetic and chemical models of carcinogenesis
  • Xenograft in nude mice