Hepatic stellate cells (HSCs) activating HSF1-mediated COMP secretion promote liver metastasis of pancreatic cancer through CD36/AKT/FOXM1 signaling

Abstract

efficacy as first-line treatment for metastatic pancreatic cancer (mPCa) compared to gemcitabine alone in the MPACT randomized phase III trial.[2] Real-life clinical practice , however, is comprised of diverse treatment conditions and heterogenous patient populations. Here we report on prospective, non-interventional real-world data regarding the use of nab-paclitaxel in mPCa patients (pts) in the Austrian clinical routine. Methods: Pts with confirmed mPCa who met the eligibility criteria were treated with nab-P/G at a dose regimen of nab-paclitaxel 125mg/m2 plus gemcitabine 1000mg/m2 on days 1, 8, 15 of every 28day cycle in its labeled indication until progression and prospectively observed until disease progression or unacceptable toxicity. Primary objectives were safety and tolerability of nab-paclitaxel, secondary objectives were the objective response rate (ORR) and assessment of real life dosing in daily clinical routine. Descriptive statistics were used to analyze the data. Results: Between 5/2015 and 1/2018, 237 pts (median age: 70 years, range 44-89; 55% male, 108 (46%) >70 years) were included across 20 sites, 219 pts were eligible for analysis. At baseline, 46% (67/145) had grade 2 and 46% (66/145) grade 3 disease; CA19-9 was elevated in 85% of pts (161/190). A total of 1011 treatment cycles were applied, 46% (463 cycles) on days 1/8/15, while 34% (345 cycles) were initiated at a reduced dose intensity (days 1/0/15). Median treatment duration was 4 cycles (n ¼ 219; range 1-17). Patients' performance status was ECOG 0-1 in 96% of administered cycles. The ORR of this interim analysis was conducted in 145 patients and consisted of 43% partial responses (PR), 41% had stable disease (SD) for a disease control rate (DCR) of 83%. In the elderly cohort (>70, n ¼ 62), 45% had a PR and 42% had SD for a DCR of 87%. Median PFS was 5.1 months both in all pts (n ¼ 151) and in evaluated subgroups (/ >70 years, n ¼ 82/n¼69, HR ¼ 0.941). Nab-P/G was well tolerated with comparable rates of adverse drug reactions (495 vs. 455) in the respective subgroups (/>70 years), 86% (both) being non-serious, 13 vs. 11% required hospitalization. Pts in both subgroups benefited from the scheduled dose regimen mostly on days 1/8/15 (n ¼ 41/ n¼32) with a median PFS of 5.8 months. A less dose dense application mostly on days 1/0/15 resulted in a PFS of 6.1 vs. 5.1 months in pts 70 vs. > 70 years (n ¼ 14/n¼18; HR ¼ 0.82). The most common reasons for treatment discontinuation (n ¼ 171) were tumor progression (45%) or death in (19%); 5% of pts discontinued treatment due to toxicity. No new safety signals were identified. Conclusion: These preliminary real-world data confirm the effectiveness and tolerabil-ity of nab-P/G in the clinical routine treatment of metastatic pancreatic cancer patients including a large cohort of elderly patients >70 years. P À 035 Hepatic stellate cells (HSCs) activating HSF1-mediated COMP secretion promote liver metastasis of pancreatic cancer through CD36/AKT/FOXM1 signaling Introduction: Previous studies demonstrated that primary pancreatic cancer cells can release circulating factors or exosomes into the liver to form premetastatic niches. HSCs are important in forming premetastatic niches because they can transdifferentiate into the tumor-associated myofibroblasts, and then promote metastasis and growth of pancreatic cancer cells. The transcriptional regulator heat shock factor 1 (HSF1) is frequently activated in tumor stroma, and Cartilage oligomeric matrix protein (COMP) is a 524 kDa soluble glycoprotein particularly expressed in fibrotic conditions. However, the role of HSF1 and COMP in activated HSCs of premetastatic niches to facilitate metastasis and growth of pancreatic cancer remains to be elucidated. Methods: Elisa assay was used to detect expression of COMP in serums of pancreatic cancer patients with or without liver metastasis. Human primary HSCs and LX2 cells were activated by the conditioned medium (CMpcs) of pancreatic cancer cells (Panc-1) in vitro. The expression of HSF1, HSP90, HSP47, COMP in HSCs; CD36, p-AKT, AKT and Forkhead box M1 (FOXM1) in Panc-1 cells was determined by qRT-PCR, western blotting and immunofluorescence. CHIP-qPCR assay and dual-luciferase reporter system were used to explore the correlation between HSF1and COMP. The conditioned medium (CMhscs/lx2) of activated HSCs or LX2 was collected after treated with or without anti-COMP neutralizing antibody, KRIBB11 (an inhibitor of HSF1) or si-HSF1for 48 h, and indirect co-culture model was established to examine the effects of activated HSCs on the invasion and growth of pancreatic cancer cells. Intrasplenic tumor injection was used to establish a standard liver metastasis model of pancreatic cancer. Results: The secretion of COMP in serums is higher in pancreatic cancer patients than that in normal individuals, and it is highest in pancreatic cancer patients with liver metastasis. The expression of HSF1, HSP90, HSP47, COMP, a-SMA and collagen I were elevated in activated human primary HSCs and LX2 cells co-cultured with CMpcs. Double immunofluorescence staining showed that the expression of COMP and nuclear translocation of HSF1 was prominently enhanced in activated HSCs and LX2, and it was reversed in the presence of KRIBB11or si-HSF1. The secretion of COMP in CMhscs/lx2 of activated HSCs or LX2 was also increased. CHIP-qPCR assay and dual-luciferase reporter system showed that HSF1 can act on the promoter region of COMP. The results of indirect co-culture model displayed that CMhscs/lx2 can notably facilitate the invasion of Panc-1cells, increase the expression of EMT markers, p-AKT, FOXM1, and promote the nuclear translocation of FOXM1. These effects were reserved by silencing CD36 (a receptor of COMP), si-FOXM1, treated with LY294002