: Extracellular matrix remodelling that occurs in pancreatic ductal adenocarcinoma (PDAC) is considered a promoting factor of cancer growth, immune evasion and therapeutic resistance. Cancer-associated fibroblasts (CAFs) that constitute the dominant stromal population, arise primarily from activated pancreatic stellate cells and display remarkable functional heterogeneity, encompassing inflammatory iCAFs and contractile myCAFs. Although epithelial-stromal communication is central to PDAC biology, the upstream mechanisms that prime tumour cells toward CAF-Activating cells remain incompletely defined. The leukaemia inhibitory factor (LIF), a pleiotropic cytokine of the IL-6 family, is highly expressed in PDAC and has been implicated in tumour progression. However, the role of LIF and LIF receptor (LIFR):gp130 complex in promoting CAF activation is poorly defined. Here, we combined human PDAC transcriptomics, immunofluorescence and epithelial-stromal co-culture assays to define LIF-driven pro-CAF programs and evaluate their pharmacological reversibility. In PDAC cancer cells, MIAPaCa-2 cells, LIF induced a coordinated transcriptional network encompassing inflammatory mediators, paracrine fibroblast-activating signals and ECM/mechanotransductive modules, while repressing stromal-inhibitory genes. These signatures were recapitulated in PDAC tissues, where LIF expression directly correlated with CAF markers and with stromal remodelling genes. On this background, we have developed a novel steroidal LIFR antagonist, LRI310, and evaluate its effects on LIF:LIFR axis. Exposure of PDCA cell lines to LRI310 suppresses STAT3 activation and counteracts effects of LIF on proliferation and CAF-inducing transcriptional programs. Collectively, these findings identify LIF as an important epithelial driver of CAF-oriented transcriptional programs in PDAC and support the development of LIFR antagonism as a promising strategy to modulate the desmoplastic microenvironment.
LIFR antagonism reverses epithelial pro-CAF programs in pancreatic ductal adenocarcinoma
Giorgio, Cristina Di;Sette, Maria Rosaria;Sensini, Benedetta;Giannelli, Eleonora;Lachi, Ginevra;Paniconi, Francesca;Massa, Carmen;Urbani, Ginevra;Cartaginese, Fabio;Distrutti, Eleonora;Biagioli, Michele;Fiorucci, Stefano
2026
Abstract
: Extracellular matrix remodelling that occurs in pancreatic ductal adenocarcinoma (PDAC) is considered a promoting factor of cancer growth, immune evasion and therapeutic resistance. Cancer-associated fibroblasts (CAFs) that constitute the dominant stromal population, arise primarily from activated pancreatic stellate cells and display remarkable functional heterogeneity, encompassing inflammatory iCAFs and contractile myCAFs. Although epithelial-stromal communication is central to PDAC biology, the upstream mechanisms that prime tumour cells toward CAF-Activating cells remain incompletely defined. The leukaemia inhibitory factor (LIF), a pleiotropic cytokine of the IL-6 family, is highly expressed in PDAC and has been implicated in tumour progression. However, the role of LIF and LIF receptor (LIFR):gp130 complex in promoting CAF activation is poorly defined. Here, we combined human PDAC transcriptomics, immunofluorescence and epithelial-stromal co-culture assays to define LIF-driven pro-CAF programs and evaluate their pharmacological reversibility. In PDAC cancer cells, MIAPaCa-2 cells, LIF induced a coordinated transcriptional network encompassing inflammatory mediators, paracrine fibroblast-activating signals and ECM/mechanotransductive modules, while repressing stromal-inhibitory genes. These signatures were recapitulated in PDAC tissues, where LIF expression directly correlated with CAF markers and with stromal remodelling genes. On this background, we have developed a novel steroidal LIFR antagonist, LRI310, and evaluate its effects on LIF:LIFR axis. Exposure of PDCA cell lines to LRI310 suppresses STAT3 activation and counteracts effects of LIF on proliferation and CAF-inducing transcriptional programs. Collectively, these findings identify LIF as an important epithelial driver of CAF-oriented transcriptional programs in PDAC and support the development of LIFR antagonism as a promising strategy to modulate the desmoplastic microenvironment.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
