Researching tumour recurrence

Researching tumour recurrence in regenerating livers post-hepatectomy

Foundation for Surgery scholarship recipient Dr Georgina Riddiough talks about her promising research

Dr Georgina Riddiough, a PhD candidate in the Liver Research Group at the Austin precinct of the Department of Surgery, University of Melbourne, and an Austin Health surgical registrar, was awarded the Royal Australasian College of Surgeons (RACS) Reg Worcester Research Scholarship in 2019. It is an honour she has put to good use. The scholarship provided her with the opportunity to research tumour recurrence in regenerating livers posthepatectomy, and the findings are very encouraging. The liver’s ability to regenerate after hepatectomy is well-known but, unfortunately, failing to identify a small cancer because it can’t be seen on a scan, or because it gets left behind, means it may “grow significantly during the regenerative process”, Dr Riddiough said. “A lot of the processes that drive liver regeneration are linked to how tumours grow and how organs grow in the uterus when we’re developing – so if you’ve got cancer hanging around it can be a risky process.” For the liver to regrow, cells have to proliferate, blood vessels and new lymphatics form – and all of these things are exactly what cancer is trying to do, she explained. “The regenerating liver creates a perfect storm.” Using mouse models, Dr Riddiough induced colorectal liver metastasis and then hepatectomised, removing 70 per cent of their liver, in order to try and understand how the tumour progressed in the regenerating liver. She then looked at whether renin-angiotensin inhibitors (RASi) could attenuate the progression of the tumour, and found that they did, indeed, slow the progression of the tumour in the regenerating liver. “Importantly, we showed they were safe to administer within the immediate postoperative phase and in that very early regenerative phase,” Dr Riddiough said. “At the moment if you undergo any cancer resection, we will not administer chemotherapy during that immediate post op time because the body is healing.” However, this drug, which has been around for about 20 years and is FDA-approved to treat hypertension and cardiac failure, is slowing the tumours at this critical phase. “The drug doesn’t make the tumour melt away or vanish, but it does significantly reduce the tumour burden in mice,” Dr Riddiough said. “Obviously, we wanted to know how it was doing this, so we delved in and a couple of interesting findings emerged.” The first was that the RASi appear to completely switch the immune response on its head. Cancer grows by “manipulating the immune landscape of its environment so it can hide from T cells that would normally attack and kill cancers,” Dr Riddiough explained. “It also uses another arm of the immune system – myeloid-derived suppressor cells (MDSC) – to dampen the normal immune responses that would kill the cancer.” In one respect, she said, the cancer uses MDSC to make the tumour microenvironment more immunosuppressive and, in another respect, it switches off some of the functions of these cytotoxic T cells that normally kill cancer cells. “We found that RASi actually enhance the T cell response while dampening the immunosuppressive effects of MDSC.” The drug specifically enhanced a specific population of liver-resident T cells, Dr Riddiough said. The drug was also enhancing the population of T cells that express a marker called PD-1, which is the marker for activation. “It’s an important marker because people have tried to target it for immunotherapy and there’s a lot of emerging evidence surrounding the anti-tumour functions of these tissueresident T cells, which have been a bit neglected,” Dr Riddiough said. “Their role in anti-tumour immunity hasn’t been fully appreciated.” A second novel finding was the discovery that the mice being treated with RASi “had changes in expression of some of the target genes of the Wnt/ß-catenin pathway, which is central to the development of colorectal cancers ... and that was pretty exciting,” Dr Riddiough said.

The final part of Dr Riddiough’s PhD research will be translating the findings into human settings. She is working with liver surgeons at the Austin Hospital and scientists at the Doherty Institute to obtain small samples of both tumours and livers from consenting patients and establish organoid cultures. In the lab Dr Riddiough has processed the samples and established patient-derived organoids. “We’ve tested the drug on human colorectal liver metastasis organoids and it also suppresses their growth,” she said. 