Researchers identify a previously unknown mechanism that can drive cancer cachexia

Researchers at Helmholtz Munich, the Heidelberg Faculty of Medicine at Heidelberg University, the German Center for Diabetes Research (DZD) and the Technical University of Munich (TUM), have identified a previously unknown mechanism that can drive cancer cachexia – a wasting process in the body that primarily affects muscle and fat tissue. A central role is played by a protein secreted by tumors, known as ADAMTSL4: It locally activates the TGF-β signaling pathway in muscle and fat tissue, thereby triggering a catabolic program. The findings identify ADAMTSL4 as a potential new target for future therapies against cancer cachexia. The researchers publish their results today in Cancer Discovery, a journal of the American Association for Cancer Research.

Many cancer patients lose substantial weight during the course of their disease. This is not only because they eat less. Rather, tumors can actively trigger wasting processes in the body. These processes primarily affect muscle and fat tissue. Cancer cachexia further weakens patients and often complicates treatment: Patients frequently respond less well to therapies and experience a reduced quality of life. Although cancer cachexia contributes substantially to disease burden, there is currently no approved pharmacological therapy.

Elevated ADAMTSL4 levels in cachectic patients with colorectal and lung cancer

We wanted to better understand which signals from the tumor trigger the breakdown of muscle and fat tissue."

Dr. Mauricio Berriel Diaz, last author of the study and research group leader, Institute for Diabetes and Cancer (IDC), Helmholtz Munich

The team focused on ADAMTSL4, a protein released by tumor cells. In several mouse models of cancer cachexia, the researchers found elevated ADAMTSL4 levels in the blood. Higher ADAMTSL4 levels were also associated with greater weight loss and more pronounced cachexia in patients with colorectal and lung cancer.

To test whether ADAMTSL4 is indeed involved in the development of cachexia, the team specifically altered the amount of the protein in mouse tumor cells. When they switched off ADAMTSL4 production in tumor cells that normally induce cachexia, the animals lost significantly less muscle and fat mass. Conversely, when the researchers increased ADAMTSL4 production in tumor cells that otherwise do not cause cachexia, these cells formed cachexia-inducing tumors. "This allowed us to show that ADAMTSL4 is not merely associated with cachexia, but can actively drive the process," says Dr. Juliano Machado, first author of the study and postdoc at the IDC.

ADAMTSL4 locally activates the TGF-β signaling pathway

In the next step, the team investigated how ADAMTSL4 exerts this effect. They found that the protein does not directly activate the breakdown of muscle and fat tissue, but rather acts through a known signaling pathway. On the surface of muscle cells, TGF-β1 – an important messenger for cell and tissue remodeling – is initially present in an inactive form. ADAMTSL4 binds to a component of this dormant complex and thereby releases active TGF-β1. This then activates signaling pathways that promote protein breakdown in muscle cells and enhance fat breakdown in adipocytes.

This mechanism is particularly interesting for the development of potential therapies because directly blocking TGF-β is therapeutically challenging. The signaling pathway fulfills many important functions in the body; systemic inhibition could therefore be associated with considerable side effects. ADAMTSL4 may offer a way out of this dilemma: The protein is secreted by tumors, is elevated in cachexia, and appears to activate TGF-β locally in the affected tissues. "Instead of systemically blocking TGF-β itself, we could in the future try to specifically inhibit an upstream tumor factor – ADAMTSL4," says Prof. Stephan Herzig, Director of the IDC. "This makes ADAMTSL4 a promising target for the development of new anti-cachectic therapies."

Further investigation of ADAMTSL4 as a potential therapeutic target

At the same time, Berriel Diaz emphasizes that cancer cachexia is not a uniform process: "ADAMTSL4 levels are unlikely to be equally elevated in all patients; appetite regulation, inflammatory processes, and other tumor factors may also play a role." The findings therefore also point toward personalized therapeutic strategies: In the future, it may be possible to identify patients with elevated ADAMTSL4 levels for whom targeted blockade of this signaling pathway could be particularly useful.

"The results provide a basis for further investigating ADAMTSL4 as a therapeutic target," Berriel Diaz concludes. "Looking ahead, it will be important to determine whether targeted inhibition of this factor can slow the loss of muscle and fat tissue in cancer cachexia."

"M1 Cachexia Center" to unite Munich's cancer cachexia research

With the "M1 Munich Medicine Alliance", a new consortium is being established to bring together top-tier biomedical research in Munich. In its inaugural "Innovations for Patients" funding round, researchers at Helmholtz Munich – together with clinical partners at the Technical University of Munich (TUM) and Ludwig Maximilian University Munich (LMU) – secured substantial funding to establish the "M1 Cachexia Center". The center provides an important framework for developing new therapeutic approaches to cancer cachexia, an endeavor to which the present study will contribute.