Combined targeting of AGR2/IGF1-mediated paracrine and reciprocal signaling for pancreatic cancer therapy

• Applicant: Privatdozent Bo Kong, Ph.D.
• Subject Area: Cell Biology ; Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513617385

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with extensive desmoplasia being a prominent feature. PDAC cells actively communicate with cancer-associated fibroblasts (CAFs) in a paracrine/reciprocal manner, which synergistically promotes tumour progression and desmoplastic reaction. Thus, it is crucial to decipher the molecular machinery underlying this detrimental crosstalk. Hereby, we report that AGR2 (anterior gradient 2), an endoplasmic reticulum (ER)-resident protein disulfide isomerase, is secreted by PDAC cells to activate CAFs via hedgehog (Hh) receptor and/or Wnt signaling pathway in a paracrine manner while CAFs return a reciprocal signal with IGF1 (insulin-like growth factor 1) to PDAC cells to further enhance AGR2 transcription via IGF1R/c-Jun axis. Moreover, intracellular AGR2 acts as thioredoxin that facilitates IGF1R presentation to the cell surface of PDAC cells and extracellular AGR2 promotes IGF1-induced activation of IGFIR by increasing mTORC2 activity in an autocrine manner, ensuring the activity of the IGF1R/c-Jun axis. As such, tumour-derived paracrine AGR2 and CAFs-derived reciprocal IGF1 signaling form a vicious circle at multiple levels exacerbating desmoplastic reaction and tumorigenesis. Accordingly, the combined targeting of both signals effectively interrupts the crosstalk, reduces desmoplastic reaction, and reconstitutes anti-tumour immunity (potentially Th2-mediated humoral immune response) in transgenic mouse models. Altogether, we anticipate that the combined targeting of AGR2/IGF1-mediated paracrine and reciprocal signal constitutes a potential therapeutic strategy against PDAC.

• DFG Programme: Research Grants