Written by Bethany Hoernfeldt, Science Writer
Scientists have revealed a novel mechanism in chemoresistance that may inspire unique approaches to cancer treatment.
Irinotecan (Iri) is a popular chemotherapeutic agent used in the treatment of metastatic colorectal cancer. However, its efficacy is often compromised by drug resistance. In a recent study, researchers sought to demystify the mechanisms that underpin drug resistance in Iri-resistant tumour cells. Using a single-cell mass spectrometry (SCMS) method on colon cancer cells, they identified SCD1 overexpression as the culprit.
Studies that show the molecular and metabolic signatures of early-stage drug-resistant tumour cells are few and far between. Luckily, this study provides a deeper understanding of the drug resistant mechanisms of rare cancer cells, which will hopefully propel us one step closer to a cancer-free world.
With great power comes great risk
Chemotherapy is a ground-breaking treatment option for cancer and, in an ideal world, it would come without risks. Unfortunately, its success is often limited by drug resistance. Chemotherapy itself is a selective pressure that, at times, leaves behind resistant cancer cell subpopulations with less competition for space and resources. In addition, treatments such as chemotherapy are known to occasionally transform normal cells into cancer stem cells (CSCs), which are a subpopulation within tumours that are capable of self-renewal and can cause recurrences. Ironically, CSCs are more prone to drug resistance than others, further continuing the cycle.
A little-known cause of cancer drug resistance
The scientists used a SCMS method dubbed “single probe” to identify metabolic differences between HCT-116 colorectal cancer cells and their Iri-resistant counterparts. Single-probe is a multi-purpose device that prepares the contents of single cells for real-time mass spectrometry measurement. Unlike mass spectrometry – a popular tool for metabolomics studies of live cells – it is effective in experiments involving heterogeneous samples that contain very few target cells. Using single-probe and other analytical techniques, such as flow cytometry and western blotting, they found that the drug-resistant cells contained an unusually high ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs). This then shifted their attention toward a little-known drug-resistance mechanism: The overexpression of stearoyl-CoA desaturase-1 (SCD1).
An unlikely culprit
In recent years, SCD1 – an enzyme that catalyses SFAs into MUFAs – has become a target of cancer genomics studies. However, few researchers have questioned its involvement in drug resistance. In normal cells, SFAs and MUFAs are vital components of cell membranes and signalling molecules, but higher levels of MUFAs are implicated in certain types of cancers, as they can stimulate tumourigenic pathways.
Upon further investigation, SCD1 was also found to upregulate ALDH1A1 – a stem cell biomarker of colon cancer. It plays a central role in cellular detoxification and protects cells from destructive reactive oxygen species (ROS), such as nitric oxide and hydrogen peroxide. ROS are typically prevalent in tumour cells, but higher amounts can induce oxidative stress and apoptosis. Several chemotherapy drugs, including doxorubicin and mitomycin c, employ that method, but their efforts are thwarted when the overproduction of ALDH1A1 decreases ROS levels to manageable limits.
Thankfully, this study provides valuable insight into the mechanisms that underlie drug resistance. This in turn may provide avenues for further research into novel therapeutic agents, and opportunities for improved disease management. Furthermore, this methodology could also be expanded to other types of drug-resistant cells. The opportunities are vast. In an ideal world, cancer diagnoses would no longer strike fear into our hearts. That reality may still be out of grasp, but armed with knowledge and time, we can accomplish anything, one step at a time.
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