Author ORCID Identifier
https://orcid.org/0000-0003-2141-5267
Date of Graduation
8-2024
Document Type
Thesis (MS)
Program Affiliation
Quantitative Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Raghu Kalluri
Committee Member
Linghua Wang
Committee Member
Navin,Nicholas
Committee Member
Ken Chen
Committee Member
Fuentes Jr.,Natividad Roberto
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and exhibits aggressive progression patterns, resists conventional treatments, and poses significant challenges to patient survival, necessitating urgent research and development of novel therapeutic approaches. Understanding cancer-associated fibroblasts (CAF) metabolism reprogramming in PDAC tumor microenvironment (TME) may uncover novel therapeutic targets. Here, we used single cell and spatial transcriptomics to comprehensively characterize the TME content of human PDAC. We characterized CAFs metabotypes and a novel CAF population expressing DPEP1, COMP, CST1, which involved in glutathione metabolism, termed "gluCAFs” and was associated with poor clinical outcomes and advanced PDAC stages. We also validate the existence of DPEP1+CAF by multiplex immunofluorescence (IF) staining. The inhibition of KRASG12D and a combination therapy involving a Hedgehog inhibitor, Gemcitabine/Abraxane, and anti-CTLA4 can reprogram DPEP1+CAFs in the PDAC TME. Our study presents a high-resolution atlas of PDAC TME and highlights DPEP1+CAFs as a novel CAF subtype critical for PDAC progression and susceptibility to KRAS inhibitors and immunotherapy.
Keywords
Pancreatic ductal adenocarcinoma; Single cell RNA transcriptomics; Spatial transcriptomics; Tumor microenvironment; Cancer-associated fibroblast; Metabotype; Dipeptidase 1; Glutathione metabolic process