Single cell and spatial analysis characterize metabolic DPEP1+ fibroblasts in PDAC

<p>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 KRAS^G12D 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.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2024

Authors dc:creator

• Zhu, Yuanyuan
• <p>https://orcid.org/0000-0003-2141-5267</p>

Contributors dc:contributor

• Raghu Kalluri
• Linghua Wang
• Navin,Nicholas

• Pancreatic ductal adenocarcinoma; Single cell RNA transcriptomics; Spatial transcriptomics; Tumor microenvironment; Cancer-associated fibroblast; Metabotype; Dipeptidase 1; Glutathione metabolic process
• Biomedical Informatics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1388

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2445