GPCRs and Fibroblast Heterogeneity in Fibroblast-Associated Diseases

G protein-coupled receptors (GPCRs) are the largest and most diverse class of signaling receptors. GPCRs regulate many functions in the human body and have earned the title of most targeted receptors . About one-third of the commercially available drugs for various diseases target the GPCRs. Fibroblasts lay the architectural skeleton of the body, and play a key role in supporting the growth, maintenance, and repair of almost all tissues by responding to the cellular cues via diverse and intricate GPCR signaling pathways. This review discusses the dynamic architecture of the GPCRs and their intertwined signaling in pathological conditions such as idiopathic pulmonary fibrosis, cardiac fibrosis, pancreatic fibrosis, hepatic fibrosis, and cancer as opposed to the GPCR signaling of fibroblasts in physiological conditions. Understanding the dynamics of GPCR signaling in fibroblasts with disease progression can help in the recognition of the complex interplay of different GPCR subtypes in fibroblast-mediated diseases. This review highlights the importance of designing and adaptation of next-generation strategies such as GPCR-omics, focused target identification, polypharmacology, and effective personalized medicine approaches to achieve better therapeutic outcomes for fibrosis and fibrosis associated malignancies

Examining CAF Heterogeneity in Pancreatic Cancer

This thesis delves into the complexities of pancreatic ductal adenocarcinoma (PDAC) and its microenvironment. This study centers on unraveling the heterogeneity of pancreatic cancer-associated fibroblasts (CAFs) using a panel of patient-derived pancreatic fibroblasts. Additionally, it delves into the realm of G-protein-coupled receptors (GPCRs), with a specific emphasis on the Endothelin receptors (ETAR and ETBR), all within the context of PDAC. A key achievement is the development of immortalized patient-derived pancreatic fibroblasts (iPDPFs), replicating CAF heterogeneity in PDAC. The iPDPFs were able to recapitulate the PDAC CAF heterogeneity, plasticity, and the overlapping nature of the tumor stroma. Functional characterization of iPDPFs highlighted their roles in ECM remodeling, cancer cell proliferation, and chemoresistance. In vivo studies showed iPDPFs\u27 ability to modify the PDAC microenvironment, affecting drug perfusion and immune cell infiltration. The research also explored GPCRs in various diseases, revealing their temporal expression patterns and therapeutic potential. Specific GPCR profiles were identified for different CAF subtypes, offering tailored treatment prospects. Within the PDAC microenvironment, the Endothelin Axis (ET-axis), particularly GPCRs ETAR and ETBR, played a multifaceted role, influencing ECM remodeling and promoting pro-tumorigenic functions. In summary, this thesis enhances our comprehension of CAF heterogeneity using iPDPFs, elucidates GPCR implications in disease contexts, and highlights the ET-axis\u27s significance in the PDAC microenvironment. Future research directions include refining the iPDPF model, validating promising GPCR discoveries, expanding into diverse disease scenarios, and deepening our understanding of the ET-axis. These efforts collectively strive towards the advancement of personalized PDAC treatments