Journal News

MCP: Proteome profiling dissects variations in tumors

Saddiq Zahari
April 1, 2018

It is well established that tumors, even those of the same type, exhibit differences in genetics and morphology. This heterogeneity not only exists for tumors from different patients but also across regions within the same tumor. The latter, termed intratumoral heterogeneity, is of particular interest because it directly affects diagnosis and prognosis.

This microscopic photo shows tumor cells from a fine needle aspiration cytology smear of a liver mass. Tumor cells exhibit nuclear enlargement, opened chromatin and multiple nucleoli.Courtesy of Jian-Hua Qiao/NIH flickr

Martin Beck and others at the European Molecular Biology Laboratory study intratumoral heterogeneity. “This has important implications for tumor development because certain cells might be more aggressive than others,” Beck said.

Most studies have looked at intratumoral heterogeneity at the genomic level. It remains largely unknown to what extent the local proteome of tumors intrinsically varies. In a new study in Molecular & Cellular Proteomics, Beck and a group of researchers at the EMBL attempt to answer this question. “We were interested to find out if the proteins contained within individual cells of the tumor are the same or different,” Beck said. Since heterogeneity in the tumor microenvironment, such as the presence of a neighboring blood vessel, may drive genetic changes, he reasoned that it might also be reflected on the level of proteins.

The researchers looked at hepatocellular carcinoma, or HCC, the most common type of liver cancer. They used HCC samples biopsied from patients and then formalin-fixed and paraffin-embedded on microscope slides. Such samples, commonly referred to as FFPE, preserve the integrity of the tissue architecture of the original tumor, allowing the researchers to study the spatial differences in protein expression.

FFPE samples, however, present technical challenges for proteomic analysis, particularly because only a limited amount of proteins can be extracted. To overcome this problem, the researchers developed a novel method that efficiently extracts proteins from FFPE samples. To profile the spatial expression of proteins, they combined this method with a technique called laser-capture microdissection to carve out microscopic regions within the tumor. The extracted proteins then were run on a mass spectrometer for identification.

The researchers first looked at the differences of protein expression between the tumor tissue and the normal tissue immediately adjacent to it. They detected consistent changes of multiple proteins known to be associated with HCC. More importantly, they also identified a few proteins that previously were not known to be HCC-related, opening possibilities for candidate biomarker development. Among these were members of the NADH dehydrogenase complex I. This finding was striking because the researchers showed that the changes were not reflected at the gene expression level, underscoring the importance of proteome profiling.

The researchers went deeper and dissected different regions within the tumor bulk. Here they found significant variations in expression of multiple proteins between areas from the center and the periphery of the tumor. “We could show that even between seemingly identical cells, with the same morphology and the same genome, there are surprisingly pronounced differences on the level of the proteins,” Beck said.

These spatial differences of protein expression include proteins that have previously been identified as HCC biomarkers. “In our analysis, we saw that even proteins that have been proposed as such biomarkers are not evenly distributed across the tumor,” Beck said.

This finding is of immediate clinical importance. Only a small fraction of a tumor can be obtained in a diagnostic or pretreatment biopsy, and thus the region of withdrawal could have a direct impact on the acquired expression profile. “It is possible that the tissue sample taken during biopsy does not reflect the actual state of the entire tumor,” Beck said.

Beck believes the method developed in this study not only allows for studying intratumoral heterogeneity but also can improve cancer proteomics research in general. “Proteomic intratumoral heterogeneity should be taken into account for future cancer research,” he said, “for example in the design of biomarker discovery experiments.”

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition weekly.

Learn more
Saddiq Zahari

Saddiq Zahari is the editor for manuscript integrity at MCP.

Related articles

From the journals: MCP
Elisabeth Adkins Marnik
From the journals: MCP
Sephra Rampersad
From the journals: MCP
Nivedita Uday Hegdekar
From the journals: MCP
Nivedita Uday Hegdekar
From the journals: MCP
Courtney Chandler

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Cracking the recipe for perfect plant-based eggs
News

Cracking the recipe for perfect plant-based eggs

Dec. 8, 2024

It involves finding just the right proteins. With new ingredients and processes, the next generation of substitutes will be not just more egg-like, but potentially more nutritious.

MSU researchers leverage cryo-EM for decades-in-the-making breakthrough
News

MSU researchers leverage cryo-EM for decades-in-the-making breakthrough

Dec. 7, 2024

Lee Kroos and Ben Orlando have reported the first high-resolution experimentally determined structures of the intramembrane protease SpolVFB.

From the Journals: MCP
Journal News

From the Journals: MCP

Dec. 6, 2024

Rapid and precise SARS-CoV-2 detection using mass spec. Mapping brain changes from drug addiction. Decoding plant osmotic stress response. Read about recent MCP papers on these topics.

What seems dead may not be dead
Award

What seems dead may not be dead

Dec. 4, 2024

Vincent Tagliabracci will receive the Earl and Thressa Stadtman Distinguished Scientist Award at the ASBMB Annual Meeting, April 12–15 in Chicago.

'You can't afford to be 15 years behind the parasite'
Award

'You can't afford to be 15 years behind the parasite'

Dec. 3, 2024

David Fidock will receive the Alice and C.C. Wang Award in Molecular Parasitology at the 2025 ASBMB Annual Meeting, April 12–15 in Chicago.

Elucidating how chemotherapy induces neurotoxicity
Award

Elucidating how chemotherapy induces neurotoxicity

Dec. 2, 2024

Andre Nussenzweig will receive the Bert and Natalie Vallee Award at the 2025 ASBMB Annual Meeting, April 12–15 in Chicago.