Abstract 406P
Background
The stroma of many types of human solid tumors, including non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC), is characterized by a pronounced desmoplastic response produced by carcinoma-associated fibroblasts (CAFs). Systemic chemotherapy (CT) can promote the oncogenic functions of CAFs through stromal-epithelial paracrine signaling. Whether systemic CT-induced alterations in CAFs affect tumor progression and treatment response remains incompletely understood.
Methods
Transcriptomic analysis in combination with Micro-Western Array (MWA) proteomic screening was used to identify epigenetic factors that are altered by CT agents in CAFs, which was followed by molecular, mechanistic, and functional studies.
Results
Systemic CT locks CAFs in a persistent pro-inflammatory and matrix-degradative state characterized by dramatic and protracted productions of IL8 and assorted inflammatory chemokines and MMP1. MWA screening of epigenetics-related proteome identified certain histone deacetylases (HDACs) and sirtuins, whose expressions decreased substantially in CT-treated CAFs. The CT-induced changes in these HDACs critically contribute to the therapy-induced CAF activation as their overexpression could significantly revert C/Tinduced secretory functions of CAFs, thereby significantly enhancing the anti-tumor efficacy of systemic CT.
Conclusions
Our findings provide novel mechanistic insights into CT-induced stroma alterations and the potential clinical implications, which may unlock clinically translatable strategies to harness these specific changes to develop a novel stroma-targeted therapy in stroma-rick solid tumors (supported by the National Science and Technology Council of Taiwan, NSTC 111-2327-B-038-075).
Legal entity responsible for the study
Taipei Medical University
Funding
National Science and Technology Council
Disclosure
The author has declared no conflicts of interest.