Biobanking Science: Growing Liver Organoids From Tumor Biopsies

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Hepatocellular carcinoma (HCC) is the most common form of liver cancer and causes over 700,000 deaths each year (1). The number of HCC cases has dramatically risen over the past two decades due to an increase in infectious hepatitis, alcohol abuse and obesity. Hepatitis B infection rates are much higher in Asian and African countries than in the rest of the world (2). Consequently, HCC deaths are 3-20 times higher in Asia than in Europe or the US (2, 3).

From the high HCC death rates, it is clear that new treatment options are needed. Currently, patients with HCC are treated by surgical resection, liver transplant, radiation, chemotherapy and/or immunooncology drugs such as Nexavar® (sorafenib), Stivarga® (regorafenib) and Opdivo® (nivolumab). However, patients with advanced or metastatic disease are not candidates for surgical treatment and available therapeutics are not effective in all patients.

Liver organoids may help find new treatments for HCC

Many researchers use cultured cell lines for drug candidate screening and preclinical research. However, these cell lines do not have the same 3D-architecture as complete organs or the same cell-to-cell signalling seen in the human body. Moreover, many cell lines have been cultured for years or decades and therefore, may no longer resemble the original tissues or tumors from which they were collected.

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To solve this problem, a number of research teams are growing 3D tissue in vitro. International Stem Cell Corporation is using human pluripotent stem cell derived-liver progenitor cells (hpLPC) to grow liver tissue in the lab.

A team of Swiss researchers is using a different approach. They recently grew liver tumor organoids from needle biopsies of HCC tumors (4). They also grew liver organoids from healthy liver tissue collected from the same patients. Tumor-derived organoids, or mini tumors, have a similar 3D structure to in vivo tumors and have been used to study breast, prostate, bladder, pancreatic and colorectal cancers.

HCC organoids are similar to their originating tumors

The Swiss researchers took biopsy samples from HCC patients and embedded them in 3D-culture plates. These cells grew into organoids with a 26% success rate. The organoids had similar structure and mutation levels to their originating tumors.

HCC tumor cells grew into compact spheroid shapes. In contrast, healthy liver cells grew into single layer cysts similar to the duct system seen in healthy livers. The lab-grown HCC organoids had similar histological structure, growth patterns and tumor markers to their originating tumors. The organoids maintained their structure when cultured for up to a year.

The researchers compared the DNA of their lab-grown organoids with the DNA of the original cancer biopsies through whole-exome sequencing. They found that the organoids had the same number of mutations as the originating tumors but had developed some organoid-specific mutations.

HCC organoids cause tumors and can be treated with Nexavar (sorafenib)

For organoids to be a good preclinical disease model, they need to behave like a real tumor. Six of the HCC organoids from this study caused tumors when injected into immunodeficient mice. Furthermore, treatment with Nexavar (sorafenib) reduced HCC organoid growth in vitro in a dose-dependent manner.

Conclusions

With newer-generation 3D-culturing techniques, labs can now culture 3D organoids from internal organs and tumors. Organoids grown from HCC tumor cells are structurally and functionally similar to their originating tumor which makes them valuable preclinical research tools. However, it takes weeks to culture organoids. Therefore, organoid culture may not be a useful way to test potential therapeutic options for each individual patient. A better approach may be to develop a large biobank of tumor-derived organoids with associated clinical data and use this research to test new potential cancer treatments.

References

1. Colombo, M and Maisonneuve, P. Controlling liver cancer mortality on a global scale: Still a long way to go. J Hepatol. 2017
2. Baecker, A. Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors. European J Canc Preven. 2018
3. Bertuccio et al. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol. 2017.
4. Nuciforo et al. Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies. Cell Rep. 2018