HSP47 is a potential dual cell target and prognostic factor in pancreatic cancer

George, Sharbeen, Estrella, Gonzales-Aloy, Janet, Youkhana, John, Kokkinos, Rosa Mistica C., Ignacio, Joshua A., McCarroll, Aparna S., Raina, Chantal, Kopecky, Jie, Liu, Amanda, Mawson, Andrea, Nunez, Cyrille, Boyer, Mert, Erkan, David, Goldstein, Koroush S., Haghighi, Paul, Timpson, Sean C., Warren, Kendelle J., Murphy, Anthony J., Gill, Amber L., Johns, Angela, Chou, Elvis, Pandzic, Sandra, Fok, Renee, Whan, Val, Gebski, Jennifer P., Morton, Minoti, Apte, Phoebe A., Phillips

Oncogene |

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a dismal 5-year survival rate at 12%. The fibrotic PDAC desmoplasia is a major contributor to chemoresistance and metastasis that drive this poor prognosis. Cancer-associated fibroblasts (CAFs) generate PDAC tumour fibrosis and have been identified as therapeutic targets to remodel the stroma to a more drug-permissive microenvironment. We assessed the therapeutic potential of inhibiting the collagen chaperone, heat shock protein 47 (HSP47) in PDAC cells and CAFs. Collagen is a key component of PDAC fibrosis and requires the activity of HSP47 to ensure correct maturation and secretion. Herein, we show that HSP47 knockdown inhibits both PDAC cells and CAF proliferation in vitro. In vivo, therapeutic HSP47 knockdown in orthotopic PDAC tumours significantly reduced intratumoural fibrosis and opened intratumoural blood vessels, while stable HSP47 knockdown specifically in CAFs additionally reduced PDAC tumour growth. We observed that HSP47 is highly expressed in the stroma of >80% of patients in a PDAC cohort (Australian Pancreatic Cancer Genome Initiative), but that it was only prognostic of poorer overall survival in the tumour compartment. Functional relevance in the tumour compartment was further validated in 3D human PDAC explants. Our work demonstrates that HSP47 is a potential therapeutic target in both PDAC cells and CAFs and represents a robust target to interfere with tumour collagen deposition.