A multidisciplinary team of researchers has identified Upd3, a cytokine, as an important modulator of tumor growth and host wasting via activation of JAK/STAT signaling.

Cancer therapy has shown immense advances over the past decade with targeted treatments that are efficacious and much safer. However, advanced cancer patients often develop cancer cachexia, a whole-body wasting syndrome. It is characterized by weight loss, anorexia and muscle atrophy.

Recent research has implicated the role of several tumor-secreted proteins that can modulate the metabolic homeostasis of muscle and adipose tissues. Neutralization of such proteins has been shown to improve cachexia symptoms. Researchers published their results in the August 17, 2021, issue of Cell Reports.

Establishing Upd3 as a mediator of tumor-host crosstalk

In earlier studies, lead author Wei Song and his colleagues had established a Drosophila model of tumor-induced organ wasting. They observed that induction of an active oncogene yorkie (yki35A), the homolog of human Yap1, caused gut tumor formation associated with organ wasting. Although they had identified several tumor-secreted proteins as regulators of host wasting, knockdown of these proteins did not affect tumor growth.

In the present study, the authors developed PathON, a web-based tool for analysis of ligands, signaling components and signature target genes for 14 common canonical Drosophila signaling pathways. They found that Jak/Stat signaling participates in tumor-host interactions and transcriptionally activates genes that cause tumor overgrowth, wasting, lipid loss and hyperglycemia.

Speaking to BioWorld Science, Song said that "hormone- or ligand-induced signaling plays a major role in interorgan communications. We hypothesized that yki-induced gut tumors produce specific ligands that activate associated signaling pathways and induce target gene expression in host organs. Our team at Wuhan along with our collaborators from Harvard developed PathON, a web-based analysis tool useful to predict the ON/OFF status of 14 major Drosophila signaling pathways. Enrichment p-values of signature target genes were calculated using a hypergeometric test."

Song is a professor at the Medical Research Institute, Wuhan University, where his group studies interorgan communication in the context of tumor-derived ligands in host wasting.

A Jak/Stat signaling ligand (Upd3) was seen to be one of the top genes upregulated in yki3SA-tumor guts by analyzing the enrichment of pathway signaling components or signature target genes. The RNA-seq dataset was obtained from the muscle of yki-tumor bearing flies, as well as a dataset from control flies, as reported in published literature.

Genetic knockdown studies to establish Upd3 significance in host wasting

Knockdown of Upd3 inhibited the downstream Jak/Stat pathway and inhibited tumor growth. Further, tumor-derived Upd3 remotely affected muscle through attenuation of the insulin response. The Jak/Stat pathway also activated insulin-like growth factors and contributed to energy imbalance, which led to cachexia.

Song added that "Our results have demonstrated that tumor-derived Upd3 not only affects muscles but also leads to systemic lipid loss and carbohydrate elevation. This Upd3/Jak/Stat pathway impaired muscle function via mitochondrial degeneration rather than enhanced protein ubiquitination."

Previous work by the group had already demonstrated that yki3SA-gut tumors also secrete ImpL2 (insulin-like growth factor binding protein [IGFBP]-related protein), leading to wasting by inhibiting systemic insulin signaling. In the present study, the authors wanted to check whether tumor-derived ImpL2 and Upd3 are independent regulators of systemic wasting. They found that the Upd3/Jak/Stat signaling induced ImpL2 expression in the host organ and promoted cachexia.

Song contends that "our study provides a novel understanding of Jak/Stat cascade in muscle physiology in Drosophila that could be a general biological process across species."

One of the main discoveries reported in this publication is the development of the PathON enrichment analysis tool that can evaluate enrichment of all potential target genes rather than single ones. Using PathON, the authors uncovered the Upd3/Jak/Stat signaling pathway as an important mediator in the tumor-host crosstalk. Upd3 was seen to be sufficient to mediate yki3SA-gut tumor growth via activation of local Jak/Stat signaling in a paracrine/autocrine manner.

Song hopes to prove these results in other models and also hopes understanding these mechanisms of cancer cachexia and targeting the Jak/Stat pathway might be an efficient treatment strategy for advanced cancers with impaired insulin response.