NEW YORK – Independent research teams have turned to phosphoproteomic profiling to characterize molecular subtypes, clinical features, and potential vulnerabilities in gastric and prostate cancer.
For the first of the studies, published in Cell Reports on Tuesday, a team from Japan's National Cancer Center Hospital, Kyoto University, and other centers in Japan used multiplexed liquid chromatography-tandem mass spectrometry to characterize protein phosphorylation patterns in 127 pretreatment gastric cancer samples and normal adjacent tissue from 73 individuals with stage I to stage IV gastric cancer.
The samples were collected by endoscopic biopsy and frozen in liquid nitrogen within 20 seconds of being collected, the team explained. In addition, they collected serial biopsy samples from nine advanced gastric cancer cases before, during, and after progression on second-line chemotherapy.
Their analysis revealed proteomics-based gastric cancer subtypes and progression patterns. "[T]his proof-of-concept study demonstrates that our method of phosphoproteome analysis of cancer cells using fresh-frozen endoscopic biopsy specimens is capable of not only defining cancer subtypes, but also capturing dynamic cancer signaling changes due to treatment," co-senior and co-corresponding authors Jun Adachi, a researcher with the National Institutes of Biomedical Innovation, Health, and Nutrition at Kyoto University, and Narikazu Boku, an investigator at the National Cancer Center Hospital and the University of Tokyo, and their colleagues wrote.
In particular, the researchers tracked down subtypes marked by oxidative phosphorylation (OXPHOS), proliferative, and epithelial-mesenchymal transition (EMT) features, which represented 50 percent, 35 percent, and 15 percent of the treatment-naïve gastric cancer cases, respectively.
Their results also highlighted treatment-related changes in subtypes including progression to more EMT-like features, as well as potential treatment targets for the EMT subtype, which was previously linked to poor outcomes.
In the EMT-enriched "subtype 2," for example, the team saw higher-than-usual expression of mesenchymal and neutrophil markers, along with enhanced activity of an AXL kinase and a GAS6 ligand, prompting a series of experiments on the use of a combination treatment that included the AXL tyrosine kinase inhibitor (TKI) in gastric cancer cell lines and xenograft mouse models. The treatment "had additive anticancer effects on mesenchymal [gastric cancer] cell lines and xenograft models," the researchers reported.
For a paper published in PNAS this week, meanwhile, investigators at Shanghai's Second Military Medical University, the Chinese Academy of Sciences, and other centers in China used tandem mass spec to profile paired prostate cancer and matched normal samples from 41 Chinese individuals with localized prostate cancer — a subset of the participants assessed using genome sequencing, transcriptomic sequencing, and DNA methylation analyses for the broader Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA).
"By scrutinizing alterations in proteins, their expression, activities, and genetic information, we aim to shed light on the molecular mechanisms driving prostate cancer development, progression, and variations across ethnic populations," the authors wrote.
Based on profiles for 10,602 proteins and nearly 21,700 phosphorylation sites on more than 5,800 proteins, the investigators identified three proteomic cancer subtypes with distinct molecular and clinical features. "Notably, these proteomic subtypes exhibited a parallel degree of heterogeneity in the phosphoproteome, featuring unique metabolism, proliferation, and immune infiltration characteristics," they wrote.
Along with efforts to focus in on protein-based biomarkers for predicting recurrence-free prostate cancer survival, members of that team looked at the possibility of targeting an SRPK1 kinase that regulates phosphorylation of a serine/arginine-rich splicing factor 1 (SRSF1) with an inhibitor called SPHINX31, based on SRPK1 and SRSF1 ties to the prostate cancer S-II subtype.
Together, the authors suggested, the work "provides valuable resources for understanding the molecular mechanisms of prostate cancer within the Chinese population, which have the potential to promote the development of personalized treatment strategies and enhance prognostic analyses for prostate cancer patients."