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Bringing Down Cancer Aircraft: Searching for Essential Hypomutated Proteins in Skin Melanoma.

Pyatnitskiy M, Karpov D, Poverennaya E, Lisitsa A, Moshkovskii S - PLoS ONE (2015)

Bottom Line: Wald reasoned that parts with no bullet holes on the airplanes returned to the airbase from a combat flight are the most crucial ones for the airplane functioning: a hit in one of these parts downs an airplane, so it does not return back for the survey.The Gene Ontology analysis revealed enrichment of essential proteins related to membrane and cell periphery.Another finding is the overrepresentation of semaphorin receptors, which can mediate distinctive signaling cascades and are involved in various aspects of tumor development.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Chemistry, 119121, Pogodinskaya str, 10, Moscow, Russia.

ABSTRACT
We propose an approach to detection of essential genes/proteins required for cancer cell survival. A gene is considered essential if a mutation with high impact upon the function of encoded protein causes death of the cancer cell. We draw an analogy between essential cancer proteins and well-known Abraham Wald's work on estimating the plane critical areas using data on survivability of aircraft encountering enemy fire. Wald reasoned that parts with no bullet holes on the airplanes returned to the airbase from a combat flight are the most crucial ones for the airplane functioning: a hit in one of these parts downs an airplane, so it does not return back for the survey. We have envisaged that the airplane surface is a cancer genome and the bullets are somatic mutations with high impact upon protein function. Similarly we propose that genes specifically essential for tumor cell survival should carry less high-impact mutations in cancer cells compared to polymorphisms found in normal cells. We used data on mutations from the Cancer Genome Atlas and polymorphisms found in healthy humans (from 1000 Genomes Project) to predict 91 protein-coding genes essential for melanoma. These genes were selected according to several criteria, including negative selection, expression in melanocytes and decrease in the proportion of high-impact mutations in cancer compared with normal cells. The Gene Ontology analysis revealed enrichment of essential proteins related to membrane and cell periphery. We speculate that this could be a sign of immune system-driven negative selection of cancer neo-antigens. Another finding is the overrepresentation of semaphorin receptors, which can mediate distinctive signaling cascades and are involved in various aspects of tumor development. Cytokine receptors CCR5 and CXCR1 were also identified as cancer essential proteins and this is confirmed by other studies. Overall, our goal was to illustrate the idea of detecting proteins whose sequence integrity and functioning is important for cancer cell survival. Hopefully, this prediction of essential cancer proteins may point to new targets for anti-tumor therapies.

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Hypothetical scheme for negative selection against neoantigens derived from cell surface proteins.Preferential involvement of surface proteins to MHC-restricted antigen presentation is known in the art [20]. Cancer cells exposing MHC-II epitopes with mutated antigens are more likely to be eliminated by T-cell mediated immune surveillance.
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pone.0142819.g004: Hypothetical scheme for negative selection against neoantigens derived from cell surface proteins.Preferential involvement of surface proteins to MHC-restricted antigen presentation is known in the art [20]. Cancer cells exposing MHC-II epitopes with mutated antigens are more likely to be eliminated by T-cell mediated immune surveillance.

Mentions: The enrichment of 91 essential protein subset by Gene Ontology [16], KEGG [17] and PharmGKB drug target [18] categories had shown a significant trend towards membrane proteins, specifically, proteins of plasma membrane and cell periphery (Fig 3, S2 Table). Obviously, such general categories cannot fully decipher possible molecular pathways or cell proliferation mechanisms. However, there may be a mechanistic interpretation of the overrepresented plasma membrane proteins. It is widely recognized that cancers escape from host immunity through evolution of cancer clones [19]. We have hypothesized that one of the mechanisms leading to conservation of plasma membrane and cell periphery protein sequence in melanoma could be a result of such immune escape. More specifically, high impact mutations in cell periphery and plasma membrane proteins may lead to formation of major histocompatibility complex (MHC) II-dependent neo-antigens [20]. MHC II-restricted protein epitopes reactive to T-helper lymphocyte subpopulation, as widely known, are formed by digestion of phagocytized extracellular proteins and cell periphery proteins accompanying internalized membrane parts. The fact that such mutations are depleted in cell surface and periphery proteins reflects escape of melanoma cells from CD4+-T-cell mediated immunity. Recently it has been reported that adoptive immunity induced against a T-helper-1 (MHC II-restricted) neo-antigen epitope provided tumor regression in a patient with metastatic cholangiocarcinoma [21]. Significant response of CD4+-T-cells against personalized tumor neo-epitopes was also found in patients with metastatic melanoma [22]. Thus, we may observe the enrichment by cell periphery proteins in target subset as a result of purifying selection against formation of neo-antigen T-helper epitopes. When a plasma membrane protein is extensively mutated in a cancer cell, it is digested after vesicle internalization and its mutant peptides bind MHC II as neo-epitopes which are not recognized by immune system as self-epitopes. Having such neo-epitopes expressed, a cancer cell cannot avoid the immune surveillance and is eliminated (Fig 4). Notably, despite MHC II itself is expressed in limited cell types, such as professional antigen-presenting cells, melanoma cells are reported to express various types of the receptor [23].


Bringing Down Cancer Aircraft: Searching for Essential Hypomutated Proteins in Skin Melanoma.

Pyatnitskiy M, Karpov D, Poverennaya E, Lisitsa A, Moshkovskii S - PLoS ONE (2015)

Hypothetical scheme for negative selection against neoantigens derived from cell surface proteins.Preferential involvement of surface proteins to MHC-restricted antigen presentation is known in the art [20]. Cancer cells exposing MHC-II epitopes with mutated antigens are more likely to be eliminated by T-cell mediated immune surveillance.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643971&req=5

pone.0142819.g004: Hypothetical scheme for negative selection against neoantigens derived from cell surface proteins.Preferential involvement of surface proteins to MHC-restricted antigen presentation is known in the art [20]. Cancer cells exposing MHC-II epitopes with mutated antigens are more likely to be eliminated by T-cell mediated immune surveillance.
Mentions: The enrichment of 91 essential protein subset by Gene Ontology [16], KEGG [17] and PharmGKB drug target [18] categories had shown a significant trend towards membrane proteins, specifically, proteins of plasma membrane and cell periphery (Fig 3, S2 Table). Obviously, such general categories cannot fully decipher possible molecular pathways or cell proliferation mechanisms. However, there may be a mechanistic interpretation of the overrepresented plasma membrane proteins. It is widely recognized that cancers escape from host immunity through evolution of cancer clones [19]. We have hypothesized that one of the mechanisms leading to conservation of plasma membrane and cell periphery protein sequence in melanoma could be a result of such immune escape. More specifically, high impact mutations in cell periphery and plasma membrane proteins may lead to formation of major histocompatibility complex (MHC) II-dependent neo-antigens [20]. MHC II-restricted protein epitopes reactive to T-helper lymphocyte subpopulation, as widely known, are formed by digestion of phagocytized extracellular proteins and cell periphery proteins accompanying internalized membrane parts. The fact that such mutations are depleted in cell surface and periphery proteins reflects escape of melanoma cells from CD4+-T-cell mediated immunity. Recently it has been reported that adoptive immunity induced against a T-helper-1 (MHC II-restricted) neo-antigen epitope provided tumor regression in a patient with metastatic cholangiocarcinoma [21]. Significant response of CD4+-T-cells against personalized tumor neo-epitopes was also found in patients with metastatic melanoma [22]. Thus, we may observe the enrichment by cell periphery proteins in target subset as a result of purifying selection against formation of neo-antigen T-helper epitopes. When a plasma membrane protein is extensively mutated in a cancer cell, it is digested after vesicle internalization and its mutant peptides bind MHC II as neo-epitopes which are not recognized by immune system as self-epitopes. Having such neo-epitopes expressed, a cancer cell cannot avoid the immune surveillance and is eliminated (Fig 4). Notably, despite MHC II itself is expressed in limited cell types, such as professional antigen-presenting cells, melanoma cells are reported to express various types of the receptor [23].

Bottom Line: Wald reasoned that parts with no bullet holes on the airplanes returned to the airbase from a combat flight are the most crucial ones for the airplane functioning: a hit in one of these parts downs an airplane, so it does not return back for the survey.The Gene Ontology analysis revealed enrichment of essential proteins related to membrane and cell periphery.Another finding is the overrepresentation of semaphorin receptors, which can mediate distinctive signaling cascades and are involved in various aspects of tumor development.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Chemistry, 119121, Pogodinskaya str, 10, Moscow, Russia.

ABSTRACT
We propose an approach to detection of essential genes/proteins required for cancer cell survival. A gene is considered essential if a mutation with high impact upon the function of encoded protein causes death of the cancer cell. We draw an analogy between essential cancer proteins and well-known Abraham Wald's work on estimating the plane critical areas using data on survivability of aircraft encountering enemy fire. Wald reasoned that parts with no bullet holes on the airplanes returned to the airbase from a combat flight are the most crucial ones for the airplane functioning: a hit in one of these parts downs an airplane, so it does not return back for the survey. We have envisaged that the airplane surface is a cancer genome and the bullets are somatic mutations with high impact upon protein function. Similarly we propose that genes specifically essential for tumor cell survival should carry less high-impact mutations in cancer cells compared to polymorphisms found in normal cells. We used data on mutations from the Cancer Genome Atlas and polymorphisms found in healthy humans (from 1000 Genomes Project) to predict 91 protein-coding genes essential for melanoma. These genes were selected according to several criteria, including negative selection, expression in melanocytes and decrease in the proportion of high-impact mutations in cancer compared with normal cells. The Gene Ontology analysis revealed enrichment of essential proteins related to membrane and cell periphery. We speculate that this could be a sign of immune system-driven negative selection of cancer neo-antigens. Another finding is the overrepresentation of semaphorin receptors, which can mediate distinctive signaling cascades and are involved in various aspects of tumor development. Cytokine receptors CCR5 and CXCR1 were also identified as cancer essential proteins and this is confirmed by other studies. Overall, our goal was to illustrate the idea of detecting proteins whose sequence integrity and functioning is important for cancer cell survival. Hopefully, this prediction of essential cancer proteins may point to new targets for anti-tumor therapies.

Show MeSH
Related in: MedlinePlus