Early detection significantly correlates with improved survival in cancer patients. So far, a limited number of biomarkers have been validated to diagnose cancers at an early stage. Considering the leading cancer types that contribute to more than 50% of deaths in the USA, we discuss the ongoing endeavors toward early detection of lung, breast, ovarian, colon, prostate, liver, and pancreatic cancers to highlight the significance of mucin glycoproteins in cancer diagnosis. As mucin deregulation is one of the earliest events in most epithelial malignancies following oncogenic transformation, these high-molecular-weight glycoproteins are considered potential candidates for biomarker development. The diagnostic potential of mucins is mainly attributed to their deregulated expression, altered glycosylation, splicing, and ability to induce autoantibodies. Secretory and shed mucins are commonly detected in patients’ sera, body fluids, and tumor biopsies. For instance, CA125, also called MUC16, is one of the biomarkers implemented for the diagnosis of ovarian cancer and is currently being investigated for other malignancies. Similarly, MUC5AC, a secretory mucin, is a potential biomarker for pancreatic cancer. Moreover, anti-mucin autoantibodies and mucin-packaged exosomes have opened new avenues of biomarker development for early cancer diagnosis. In this review, we discuss the diagnostic potential of mucins in epithelial cancers and provide evidence and a rationale for developing a mucin-based biomarker panel for early cancer detection.

Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA ( Kras ^G12D/+ Trp53 ^R172H/+ Ad-Cre ) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I–deficient tumor cells cocultured with T cells were more susceptible to T cell–mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I–knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. ST6GalNAc-I–deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I–mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.

Pancreatic cancer (PC) is characterized by metabolic deregulations that often manifest as deviations in metabolite levels and aberrations in their corresponding metabolic genes across the clinical specimens and preclinical PC models. Cholesterol is one of the critical metabolites supporting PC, synthesized or acquired by PC cells. Nevertheless, the significance of the de novo cholesterol synthesis pathway has been controversial in PC, indicating the need to reassess this pathway in PC. We utilized preclinical models and clinical specimens of PC patients and cell lines and utilized mass spectrometry-based sterol analysis. Further, we also performed in silico analysis to corroborate the significance of de novo cholesterol synthesis pathway in PC. Our results demonstrated alteration in free sterol levels, including free cholesterol, across in vitro, in vivo, and clinical specimens of PC. Especially, our sterol analyses established consistent alterations in free cholesterol across the different PC models. Overall, this study demonstrates the significance and consistency in deviation of cholesterol synthesis pathway in PC while showing the aberrations in sterol metabolite intermediates and the related genes using preclinical models, in silico platforms, and the clinical specimens.

Due to the severe toxicity posed by chemotherapeutic drugs, adjuvant nutritional intervention has gained increased attention in the treatment of pancreatic cancer (PC). Amino acid (AA) metabolism is aberrantly regulated in PC and circulating histidine (His) levels are low in PC patients. We hypothesized that His uptake and/or metabolism is dysregulated in PC and that combining His with gemcitabine (Gem), a drug used in the treatment of PC, will enhance the anti-cancer effects of Gem. We performed in vitro and in vivo studies to determine the anticancer effect of the combination of His and Gem against lethal PC. We demonstrate that circulating His levels are low in both human subjects and genetically engineered mice exhibiting pancreatic tumors. Interestingly, the expression of histidine ammonia lyase, an enzyme involved in His catabolism, is higher in PC compared to normal subjects. His + Gem exerts a more potent cytotoxic effect in PC cells compared to individual treatments. His treatment results in a profound increase in His accumulation, accompanied by a depletion of a number of AAs, promoting cancer cell survival and/or glutathione (GSH) synthesis. His but not Gem increases hydrogen peroxide and depletes cellular GSH. Supplementation with GSH protects cells against His + Gem-induced cytotoxicity. Further, our in vivo studies demonstrate that His + Gem potently reduced tumor mass and improved mouse survival. Taken together, our data suggest that PC cells exhibit an aberrant His uptake/accumulation which, in turn, leads to oxidative stress and depletion of AA pool, thereby enhancing the anticancer effect of Gem.

SERS immunoassay biosensors hold immense potential for clinical diagnostics due to their high sensitivity and growing interest in multi-marker panels. However, their development has been hindered by difficulties in designing compatible extrinsic Raman labels. Prior studies have largely focused on spectroscopic characteristics in selecting Raman reporter molecules (RRMs) for multiplexing since the presence of well-differentiated spectra is essential for simultaneous detection. However, these candidates often induce aggregation of the gold nanoparticles used as SERS nanotags despite their similarity to other effective RRMs. Thus, an improved understanding of factors affecting the aggregation of RRM-coated gold nanoparticles is needed. Substituent electronic effects on particle stability were investigated using various para-substituted thiophenols. The inductive and resonant effects of functional group modifications were strongly correlated with nanoparticle surface charge and hence their stability. Treatment with thiophenols diminished the negative surface charge of citrate-stabilized gold nanoparticles, but electron-withdrawing substituents limited the magnitude of this diminishment. It is proposed that this phenomenon arises by affecting the interplay of competing sulfur binding modes. This has wide-reaching implications for the design of biosensors using thiol-modified gold surfaces. A proof-of-concept multiplexed SERS biosensor was designed according to these findings using the two thiophenol compounds with the most electron-withdrawing substitutions: NO₂ and CN.