IL-6 Trans-Signaling and Crosstalk Among Tumor, Muscle and Fat Mediate Pancreatic Cancer Cachexia

Abstract

Most patients with pancreatic adenocarcinoma (PDAC) suffer unintentional weight loss, or cachexia. Interleukin-6 causes cachexia in mice and associates with mortality in PDAC. Here we show that tumor cell-derived IL-6 mediates crosstalk between tumor and peripheral tissues to promote cachexia. Tumor-cell IL-6 elicits expression of IL-6 in fat and IL-6 and IL-6 receptor (IL6R) in muscle, concomitantly raising both in blood. Inflammation-induced adipose lipolysis elevates circulating fatty acids, which cooperate with IL-6 to induce skeletal muscle dysmetabolism and wasting. Thus, PDAC induces crosstalk among tumor, fat and muscle via a feed-forward, IL-6 signaling loop. Tumor talks to muscle and fat through IL-6, and muscle to fat via IL6R trans-signaling, and fat to muscle through lipids and fatty acids. Disruption of this crosstalk by depletion of tumor-derived IL-6 halved fat wasting and abolished muscle loss, supporting IL-6, IL-6R and lipids as causal nodes for tissue crosstalk in PDAC cachexia.SignificancePDAC-associated cachexia significantly increases patient morbidity and mortality. This study identifies muscle and fat crosstalk via IL6R trans-signaling in concert with muscle steatosis as a main driver of PDAC-associated cachexia.

Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models

“…The CRISPR‐Cas9 system was used to generate KPC cells that are void of IL‐6 as shown in Figure 2A and as previously described 36 . The control KPC cells and the IL‐6 knockout (IL‐6 KO) cells were then plated and treated with APX compounds as well as Rux and Napa to determine their sensitivity to these agents.…”

“…Bladder cancer xenolines (BLCAb001 (RP‐B‐01) and BLCAb002 (RP‐B‐02) 31,32 ), malignant peripheral nerve sheath tumour (MPNST) cell lines (ST88‐14, S462 and NF90‐8), colon cancer lines (HCT‐116 and MC38), low passage patient‐derived human pancreatic cancer cell lines (Pa03C, Pa02C, Panc10.05 and Panc198 33 ), mouse pancreatic cancer cell lines ( LSL‐Kras G12D/+ ;LSL‐Trp53 R172H/+ ;Elas‐Cre ER : KPC2, 34 LSL‐Kras G12D/+ ;LSL‐Trp53 R172H/+ ;Pdx‐1‐Cre : KPC32043, KPC32908 35 and KPC32908‐IL‐6 knockout (IL‐6KO)) 36 and cancer‐associated fibroblasts (CAF19) were maintained at 37°C in 5% CO 2 and grown in Dulbecco's Modified Eagle's Medium (DMEM; Invitrogen) with 10% Foetal Bovine Serum (FBS; Atlanta Biologicals). ST88‐14 and S462 were received from Dr Andrew Tee (Cardiff University).…”

“…The CRISPR-Cas9 system was used to generate KPC cells that are void of IL-6 as shown in Figure 2A and as previously described. 36 The control KPC cells and the IL-6 knockout (IL-6 KO) cells were then plated and treated with APX compounds as well as Rux and Napa to determine their sensitivity to these agents. We determined that the slopes were significantly different upon comparison of the KPC32908 cells with the IL-6 KO cells (Rux and Napa: P < .05; APX compounds: P ≤ .001).…”

Targeting cancer cachexia: Molecular mechanisms and clinical study

“…Crosstalk between tumor cells and organs promotes the occurrence of cachexia. 254 Treating and delaying the progression of tumor can prolong the process of cachexia and delays cancer cachexia treatment. Tumor treatments include targeted therapy, radiotherapy, chemotherapy, and immunotherapy.…”