Demystifying cancer cachexia

I am interested in the systemic effects of cancer and disease, and to what degree disease is a perturbation of biology. The best way to really summarise the key strands in my lab at the moment is through paraneoplasia. We are looking at processes that are driven in the context of cancer through specific molecular interactions and cachexia, to my mind, is a paraneoplastic syndrome. It is essentially an adaptive process that is not sustainable, it is a biological process, not a pathobiological process. The pathobiology arises because the underlying cause is non abrogated. So, in the short term, all these hard-wired pathways make sense, but in the long term, the organism cannot support them, and so the syndrome of cachexia arises. 

We set out to trace the change in behaviour that afflicts cachexia patients, particularly their lack of impulse or volition to do the things that they would normally do, including eating. And that is noticed by the patients but also by their relatives, and is actually a significant stressor to those relationships, because relatives try to motivate them to eat their favourite food or do things that they would normally enjoy, and they seemingly don't want to do it as much as they used to and sometimes not at all. We sought to determine what might be going on there in collaboration with neuroscientists, because we suspected that was a problem encoded by the brain. 

We utilised a mouse model of cachexia and phenotyped the mice carefully in terms of their performance in effort biased foraging tasks, and we found an underperformance in the mice with cachexia. We traced the cause for this underperformance to reduced dopamine release in the nucleus accumbens, where volition and hedonic responses are encoded in dopamine. We then benefitted from the co-leadership of the work by the neuroscientists Marco Pignatelli (Washington University School of Medicine) and Adam Kepecs (Washington University School of Medicine), because that enabled a systematic tracing of the circuit of apathy in cachexia. 

The key finding is that in our mouse model of cachexia, IL-6 is sensed in the area postrema which sits in the circulating blood outside the blood brain barrier and drives a neuronal circuit from there that projects forward into the nucleus accumbens via the parabrachial nucleus. Thereby peripheral inflammation and IL-6 elevation is converted into alterations of dopamine release in the nucleus accumbens. We went on to demonstrate that if we interrupt this signalling pathway by either removing the receptor in the area postrema or antagonizing the ligand for the IL-6 receptor, through neutralizing antibodies, we see a rescue of the apathy. We also showed that if we replace dopamine specifically in the nucleus accumbens where it is depleted that is sufficient to rescue the behaviour and the foraging. 

I think it is very important to demystify the condition. And to say to people who have it that it is not their fault, that it cannot readily be overcome by wanting yourself out of it. That may seem like a minor gain therapeutically speaking, but you can imagine that that immediately has a strong impact on a whole group of patients who know that something isn't right but don't quite know why. And it's also important to be able to inform their relatives, because it's very difficult to disentangle if somebody doesn't want to do something because their brain is differently wired, or because they just want to be difficult. And that will be an immediate repercussion, that we are beginning to understand this reduced impulse to do things that you would normally do, and maybe the reduced joy that you perceive from it. 

The overarching question is, does work like ours contribute to developing better therapeutic strategies? One of the ambitions that we have within the CANCAN team is to find out if, through being able to target aspects that affect the whole organism, we are able to open up opportunities to push back harder against the tumour. That's still to be determined, but what is emerging is that there are avenues to improve nutrient intake and ways to improve nutrient processing. And thus by improving the condition of the organism, you may improve the resilience against the anti-cancer treatment, or the efficacy of the anti-cancer treatment as a consequence, thereby interrupting the cycle where the non-abrogated cancer continuously drives the repercussion for the host. One of the biggest challenges that we have in cancer treatment, one could argue, is not to kill the tumour, it is rather not to kill the organism in the process of killing the tumour. That is the true challenge, and that's a different way of looking at the problem, and the CANCAN team’s work is aiding that awareness. You cannot treat a tumour in isolation.