The worldwide incidence of colorectal cancer (CRC) is higher in men than women. However, when we delved further into incidence by lesion location, we saw that surprisingly, women have a higher incidence of tumors that occur on the right side of the colon. This correlation between lesion location and sex of the patient was really interesting to us as side matters when it comes to CRC. Patients with right-sided colon cancer (RCC) (cecum, ascending colon and hepatic flexure) have a worse overall prognosis than those with tumors on the left side (splenic flexure, descending colon, sigmoid and rectosigmoid).

In a collaboration between Yale and Memorial Sloan Kettering Cancer Center (MSKCC), we identified a valuable cohort of primary tumors collected from various locations of the colon. As the mechanisms that underlie higher RCC incidence in women, and poorer outcomes for RCC are not known, we applied mass spectrometry-based untargeted metabolomics to uncover sex differences in CRC metabolism by lesion location to uncover new mechanistic insight into these potential tumor subtypes. A majority of large tumor tissue cohort studies are derived from formalin-fixed and paraffin embedded tissue which destroys reliable measurement of metabolites. Thus experiments performed on preserved tissues (flash frozen) was extremely valuable and a strength of our study.

We found that tumors from women with RCC have a nutrient-deplete metabolic phenotype, characterized by enhanced energy production through fatty acid metabolism. We also observed elevated glutamine and asparagine production, with an increase in serine and threonine uptake, as well as increased nucleotide levels. The clinical importance of this finding was further explored in an independent data set from The Cancer Genomic Atlas, which demonstrated that high asparagine synthetase expression correlated with poorer survival for women. Of note, both high asparagine and asparagine synthetase are hallmarks for more aggressive tumors. Our work has revealed a new target for RCC in women that can be further investigated in mechanistic studies, and provides a future avenue for therapeutic investigation. Further, it highlights the value of using untargeted metabolomics approaches to generate novel hypotheses regarding disease mechanisms.

Written by Yuping Cai, Nicholas J.W. Rattray, Sajid A. Khan and Caroline H. Johnson