Our journey to unravel the interplay between genome, metabolome, and microbiome in the diagnosis and prognosis of colorectal cancer started in 2017 with the application of a Marie Skłodowska-Curie Fellowship, that started in 2019. Since then, we’ve lead seven projects for the discovery of biomarkers and their innovation process. Leading to a patent that is being prepared and will be filled before summer 2023 on two urine biomarkers of colorectal recurrence and metastasis.
So.. what is unique of Colorectal Cancer ?
Colorectal cancer (CRC) complexity resides not only in the tumorigenesis process itself but also in host-microbiome interactions. Multistep genetic mutations in oncogenes and DNA repair genes occur over time, resulting in neoplastic progression in CRC. Previous studies shown that the mutations of proto-oncogenes KRAS, NRAS, and BRAF were keys that have a significant value in CRC [1].
Microbiome has been shown to be also an important factor in the development of CRC [2]. The link between genes and the microbiome is the metabolome. Metabolites, an intermediate or end-product of metabolism, typically thought to be controlled by genetics, are also influenced by the gut microbiome. Therefore, metabolites play an essential role in the development of cancer. Even though some advances have been done in linking metabolites to genetic or microbiome origin [3], a proper link between how gene regulation is affected by the microbiome, and how the metabolites are involved in the process is lacking.
CRC and polyps have characteristic metabolites that can be detected either in the urine or faeces [4,5]. Some of the metabolites from the gut are absorbed into the circulation and eventually chemically modified (or co-metabolized) by the host, then finally excreted with the urine [6]. Analysis of faecal and urine metabolic compositions reflects the gut microbiome’s status and bridges the connections between symbiotic microbes and the host’s health. Thus, examining the faecal and urine metabolomes is a sound strategy for understanding the interactions between human metabolism, and gut microbiota composition in CRC. While several biological matrices, including saliva and blood, could be used as a source of metabolic information, urine and faeces offer some key advantages as they can be easily collected passively, non-invasively and longitudinally [7]. To date, 286 metabolites associated with CRC have been identified with metabolomics [5,8,9] in different biosamples (serum, urine, tissue and stool). However, only 76 have been found in more than one study (53-serum, 48-urine, 56-tissue and 18-stool). However, no study used FOBT samples to evaluate the metabolome from CRC and colonic polyps.
References:
[1] Stjepanovic N, et al. Ann Oncol 2019; 30:1558–71.
[2] Wong SH, et al. Nat Rev Gastroenterol Hepatol 2019;16:690–704.
[3] Diener C, et al. Nat Metab 2022;4:1560–1572.
[4] Goveia J, et al. EMBO Mol Med. 2016;8(10):1134–1142.
[5] Mallafré C, Llambrich M, Cumeras R, et al. Cancers. 2021; 13:2534. 39.
[6] Jain A, et al. Sci Rep. 2019;9:9191.
[7] Wald C. Nature. 2017;551, S48-S50.
[8] Brezmes J, Llambrich M, Cumeras R*, Gumà J. Int J Mol Sci. 2022; 23(19):11171
[9] Ni Y, et al. J Proteome Res. 2014;13(9):3857-70.
CRC outcomes:
- Urine NMR Metabolomics for Precision Oncology in Colorectal Cancer. Brezmes J, Llambrich M, Cumeras R*, Gumà J. International Journal of Molecular Sciences 2022, 23 (19), 11171. doi: 10.3390/ijms231911171.
- Comprehensive volatilome and metabolome signatures of colorectal cancer in urine: A systematic review and meta-analysis. Mallafré-Muro C†, Llambrich M†, Cumeras R*, Pardo A, Brezmes J, Marco S, Gumà J. († joint first authors) Cancers, 2021, 13(11):2534. doi: 10.3390/cancers13112534.