The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice.MethodsIsoform‐specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed‐forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes.ResultsMurine PDAC tumour‐derived cell lines expressed activin‐βA but not activin‐βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin‐low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin‐high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin‐βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not.ConclusionsPancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ‐specific and gene‐specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle‐specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene‐specific and organ‐specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

“…Moreover, as TGF-β members such as activin A, activin B, growth differentiation factor-11, and myostatin have been associated with or shown to induce skeletal muscle wasting in cancer and non-cancer settings, targeting of the ACVR2B receptor has become a promising therapeutic approach in combating cachexia. [14][15][16][17][18][19][20][21] In line with this notion, using ACVR2B/Fc, a soluble ACVR2B synthetic peptide inhibitor, our group and others have demonstrated preservation of skeletal muscle in experimental models of lung and CRC cachexia, as well as following chronic administration of several anticancer drugs. 17,[22][23][24] Moreover, targeting ACVR2B signalling has shown to preserve fat and bone mass and mildly preserve cardiac size in experimental models of cancer-induced and chemotherapy-induced muscle wasting.…”

Treatment with Soluble Activin Receptor Type IIB Alters Metabolic Response in Chemotherapy-Induced Cachexia

“…These ligands initiate their effects by binding to the activin receptor type 2B (ACVR2B). It was recently shown in a murine orthotopic model of pancreatic ductal adenocarcinoma that the tumors both express activins and induce expression in distant organs, leading to elevated levels of circulating activin [13]. Blockage of the ACVR2B receptor has therefore become a therapeutic target for the treatment of cachexia.…”

Regulatory Role of the Transcription Factor Twist1 in Cancer-Associated Muscle Cachexia

“…Our studies have shown that tumor-derived Activin A acts on the muscle to upregulate the expression of Twist1, which in turn induces the synthesis of the muscle-specific ubiquitin ligases, MuRF1 and Atrogin1, thereby causing muscle cachexia by facilitating muscle protein degradation (Figure 1; Parajuli et al, 2018). In experimental studies, serum activin levels correlated with PDAC-induced cachexia and eventual mortality (Zhong et al, 2019). In the murine model of PDAC-induced cachexia, activins (activin-βA, or Inhba) are expressed, both in tumor cells and tumor stromal cells.…”

“…Tumor-derived Activin A acts on the muscle to upregulate the expression of Twist1, which in turn induces the synthesis of the muscle-specific ubiquitin ligases (MuRF1 and Atrogin1), thereby causing cancer cachexia by facilitating muscle protein degradation (Parajuli et al, 2018). and cachexia with the resultant effect being prolonged survival (Zhong et al, 2019). Moreover, using the pharmacological drug JQ1, a small molecule that suppresses Twist1 activity by blunting its binding to MuRF1 and Atrogin1 promoters, muscle cachexia could be reversed in PDAC mice deleted of Twist1, indicating that inhibition of Twist1 activity in muscle in indispensable for preventing muscle cachexia.…”