Tumor–Stroma IL1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer

Abstract

Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor-associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NFκB. IRAK4 expression in CAF promoted NFκB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1β expression associated strongly with poor overall survival. Together, our studies establish a tumor-stroma IL1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC. Targeting the IL1β-IRAK4 signaling pathway potentiates the effect of chemotherapy in pancreatic cancer. .

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

“…We previously demonstrated that IL1/JAK/STAT signaling is the key pathway responsible for iCAF formation in PDA (Biffi et al, 2019). While a basal level of IL1 is expressed in PDA tumor cells that lack TP63 expression (Tjomsland et al, 2011;Zhang et al, 2018), a key finding in our current study is in demonstrating that a remarkable heterogeneity exists in IL1 expression in the human disease, with the highest levels being found in TP63-expressing squamous subtype tumors.…”

NO•/RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer

“…NFE2L2 encodes for Nrf2, which is a key regulator of antioxidant machinery and favors pancreatic cancer growth and progression . Similarly, cytokines including IL‐1b , IL‐6 and IL‐8 are implicated in tumorigenesis and their increased expression is associated with the development, progression and therapeutic resistance in pancreatic cancer . The role of SERPINB2 , which encodes the plasminogen activator inhibitor 2, is context‐dependent in cancer and both tumor‐suppressing and promoting functions are reported .…”

“…29 Similarly, cytokines including IL-1b, IL-6 and IL-8 are implicated in tumorigenesis and their increased expression is associated with the development, progression and therapeutic resistance in pancreatic cancer. [30][31][32][33][34][35] The role of SERPINB2, which encodes the plasminogen activator inhibitor 2, is contextdependent in cancer and both tumor-suppressing and promoting functions are reported. 36,37 However, a potential tumorsuppressive role of SERPINB2 is earlier described in pancreatic cancer.…”

Modeling Cell Communication in Cancer With Organoids: Making the Complex Simple

“…Via matrix synthesis and remodeling, they can modulate ECM stiffness and hypoxia facilitating tumor cells mobility and invasion. Through secreted molecules, such as growth factors, cytokines, chemokines and microRNAs (miRNAs), CAFs support tumor growth and induce resistance to therapy (Karagiannis et al, 2010;Zhang et al, 2018). Moreover, a direct cell-to-cell contact between CAFs and cancer cells, mediated by N-cadherin/E-cadherin adhesion complex, has been recently proved to promote tumor invasion (Labernadie et al, 2017).…”