Title: Delineating the tumor-host interactions in pancreatic cancer evolution and chemoresistance

Main supervisor: Karin Jirström

Reviewers: Göran Karlsson, Lund University and Daniel Öhlund, Umeå University

Abstract

Background

Pancreatic cancer (PC) is a devastating disease with a 5-year overall survival below 10%. Only approximately 20 % of the patients have a chance of cure through surgery followed by chemotherapy, but most tumors recur even after this procedure. For the majority of patients, palliative chemotherapy is the only treatment option, eventually leading to therapy resistance. The CHAMP study is a prospective, observational clinical study enrolling patients with PC and other periampullary cancers who receive neoadjuvant, adjuvant or palliative chemotherapy at Skåne University Hospital. Repeated on-treatment blood sampling is employed to gain insight into PC evolution and the molecular processes leading to chemotherapy resistance under the stress of systemic treatment.

Methods

In the first subproject, longitudinal blood samples from 60 patients have been analyzed by flow cytometry, proximity extension assay (PEA) and ultra-deep targeted sequencing to measure levels of circulating immune cells, serum proteins, and circulating tumor DNA (ctDNA), respectively. The genetic and immune landscapes are also investigated in paired resected tumors (n=15) and biopsies (n=24). In the second subproject, the small leucin-rich proteoglycan decorin has been analyzed by PEA in longitudinal blood samples from 100 patients. Decorin expression will also be analyzed by immunofluorescence in tissue from resected tumors (n= 23) and/or primary tumors and distant metastases collected post-mortem (n= 10). The third subproject will focus more closely on the potential role of circulating B cells in chemoresistance through transcriptomic and flow cytometric analyses.

Preliminary results

Decorin levels in serum increase following introduction of chemotherapy, and high levels at three months are associated with shorter survival. Serum- decorin levels align with cell-free DNA rather than KRAS-mutated ctDNA during chemotherapy. High circulating levels of the B cell attracting chemokine CXCL13 at one month and B cells at three months are associated with shorter survival.

Significance

With this research, we hope to learn more about the interplay between molecular events and host factors leading to chemotherapy resistance. The long-tern goal of the CHAMP study is to identify novel treatment strategies, including adaptive approaches, to combat this devastating disease, and this thesis is a part of that