UNASSIGNED: Biliary tract cancer (BTC) is associated with a dismal prognosis, partly because it is typically diagnosed late, highlighting the need for diagnostic biomarkers. The purpose of this project was to identify and validate multiprotein signatures that could differentiate patients with BTC from non-cancer controls.
UNASSIGNED: In this study, we included treatment-naïve patients with BTC, healthy controls, and patients with benign conditions including benign biliary tract disease. Participants were divided into three non-overlapping cohorts: a case-control-based discovery cohort (BTC = 186, controls = 249); a case-control-based validation cohort (validation cohort 1: BTC = 113, controls = 241); and a cohort study-based validation cohort including participants (BTC = 8, controls = 132) referred for diagnostic work-up for suspected cancer (validation cohort 2). Immuno-Oncology (I-O)-related proteins were measured in serum and plasma using a proximity extension assay (Olink Proteomics). Lasso and Ridge regressions were used to generate protein signatures of I-O-related proteins and carbohydrate antigen 19-9 (CA19-9) in the discovery cohort.
UNASSIGNED: Sixteen protein signatures, including 2 to 82 proteins, were generated. All signatures included CA19-9 and chemokine C-C motif ligand 20. Signatures discriminated between patients with BTC vs. controls, with AUCs ranging from 0.95 to 0.99 in the discovery cohort and 0.94 to 0.97 in validation cohort 1. In validation cohort 2, AUCs ranged from 0.84 to 0.94. Nine signatures achieved a specificity of 82% to 84% while keeping a sensitivity of 100% in validation cohort 2. All signatures performed better than CA19-9, and signatures including >15 proteins showed the best performance.
UNASSIGNED: The study demonstrated that it is possible to generate protein signatures that can successfully differentiate patients with BTC from non-cancer controls.
UNASSIGNED: We attempted to find blood sample-based protein profiles that could differentiate patients with biliary tract cancer from those without cancer. Several profiles were found and tested in different groups of patients. The profiles were successful at identifying most patients with biliary tract cancer, pointing towards the utility of multiprotein signatures in this context.

Autophagy is induced during differentiation of human monocytes into macrophages that is mediated by CSF1/CSF-1/M-CSF (colony stimulating factor 1 [macrophage]). However, little is known about the molecular mechanisms that link CSF1 receptor engagement to the induction of autophagy. Here we show that the CAMKK2-PRKAA1-ULK1 pathway is required for CSF1-induced autophagy and human monocyte differentiation. We reveal that this pathway links P2RY6 to the induction of autophagy, and we decipher the signaling network that links the CSF1 receptor to P2RY6-mediated autophagy and monocyte differentiation. In addition, we show that the physiological P2RY6 ligand UDP and the specific P2RY6 agonist MRS2693 can restore normal monocyte differentiation through reinduction of autophagy in primary myeloid cells from some but not all chronic myelomonocytic leukemia (CMML) patients. Collectively, our findings highlight an essential role for PRKAA1-mediated autophagy during differentiation of human monocytes and pave the way for future therapeutic interventions for CMML.