Abstract
Aberrant protein glycosylation is a prominent cancer feature. While many tumour-associated glycoepitopes have been reported, advances in glycoanalytics continue to uncover new associations between glycoproteins and cancer. Guided by a comprehensive literature survey suggesting that oligomannosylation (Man5-9GlcNAc2, M5-M9) is a widespread albeit poorly studied glyco-signature in human cancers, we here re-visit a valuable compilation of nearly 500 LC-MS/MS N-glycomics datasets acquired across 11 human cancer types to systematically test for oligomannose-cancer associations. Firstly, our quantitative glycomics data obtained across 34 cancerous cell lines demonstrated that oligomannosylation, particularly the under-processed M7-M9, is a strong pan-cancer feature. We then showed cell surface expression of oligomannosidic epitopes in the promyelocytic leukemic HL-60 cell line using concanavalin A-based flow cytometry. In keeping with literature, our quantitative glycomics data of tumour and matching control tissues and new MALDI-MS imaging data of tissue microarrays showed a strong cancer-associated elevation of oligomannosylation in both basal cell (p = 1.78 x 10-12) and squamous cell (p = 1.23 x 10-11) skin cancer and colorectal cancer (p = 8.0 x 10-4). The glycomics data also indicated that few cancer types including gastric and liver cancer exhibit unchanged or reduced oligomannose levels, observations also supported by literature and MALDI-MSI. Finally, data from cancer repositories indicated that three α1,2-mannosidases dictate oligomannose expression in cancer cells, and further suggested that deleterious mutations and reduced expression of MAN1A1 are key contributors to the cancer-associated oligomannose elevation. Collectively, these findings open hitherto unexplored avenues for the development of new cancer biomarkers and therapeutic targets.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- 2-AB
- 2-aminobenzoic acid
- ALL
- acute lymphocytic leukaemia
- AML
- acute monocytic leukaemia
- APL
- acute promyelocytic leukaemia
- APTS
- 8-amino-1,3,6-pyrenetrisulfonic acid
- Asn
- asparagine
- BC
- breast cancer
- BCC
- basal cell carcinoma
- BlaCa
- bladder cancer
- BPH
- benign prostatic hyperplasia
- BSA
- bovine serum albumin
- CC
- cholangiocarcinoma
- CLL
- chronic lymphocyte leukaemia
- CNV
- copy number variation
- ConA
- concanavalin A
- CRC
- colorectal cancer
- ER
- endoplasmic reticulum
- FF
- fresh frozen
- FFPE
- formalin-fixed paraffin-embedded
- Fuc
- fucose
- Gal
- galactose
- GC
- gastric cancer
- GEO
- Gene Expression Omnibus
- Glc
- glucose
- GlcNAc
- N-acetylglucosamine
- HCC
- hepatocellular carcinoma
- KC
- kidney cancer
- LC-MS/MS
- liquid chromatography tandem mass spectrometry
- MALDI-MSI
- matrix-assisted laser desorption / ionization mass spectrometry imaging
- Man
- mannose
- Me-α-Man
- methyl-α-D-mannopyranoside
- NeuAc
- N-acetylneuraminic acid
- OC
- oral cancer
- OvC
- ovarian cancer
- PanCa
- pancreas cancer
- PBS
- phosphate buffered saline
- PCa
- prostate cancer
- PGC
- porous graphitised carbon
- SCC
- squamous cell carcinoma
- SD
- standard deviation
- SSM
- simple somatic mutation
- TC
- thyroid cancer
- TCGA
- The Cancer Genome Atlas
- TMA
- tissue microarray