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Тоневицкий Александр Григорьевич

Факультет биологии и биотехнологии

Профиль на hse.ru ↗ тел.: +7 (495) 772-95-90 | 15093
Публикаций
92
Языков
1
Наград
8
Конференций
1
Профиль Публикации (92) Курсы (6)

Профессиональные интересы

молекулярная биологиямикрофлюидные системыбелковые молекулы

Должности

  • Декан — Факультет биологии и биотехнологии
  • Профессор — Факультет биологии и биотехнологии, Базовая кафедра Института биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова РАН
  • Главный научный сотрудник — Факультет биологии и биотехнологии, Лаборатория исследований молекулярных механизмов долголетия
  • Главный научный сотрудник — Факультет биологии и биотехнологии, Международная лаборатория микрофизиологических систем

Био

  • · Начал работать в НИУ ВШЭ в 2018 году.
  • · Научно-педагогический стаж: 18 лет.

Образование

  • 2025 · Академик РАН
  • 2006 · Член-корреспондент РАН
  • 1995 · Ученое звание: Профессор
  • 1993 · Доктор биологических наук
  • 1985 · Кандидат биологических наук
  • 1979 · Специалитет: Московский государственный университет им. М.В. Ломоносова, специальность «Биология», квалификация «Биолог»

Опыт работы

  • · 1974-1981: Российский кардиологический центр РКНПК МЗ РФ
  • · 1994: Присвоено звание профессора по специальности «Молекулярная биология»
  • · 1991-1995: Заведующий лабораторией в «Государственный НИИ генетики»
  • · 1995-1996: Заместитель директора Института иммунологии МЗ и МПРФ
  • · 1996-2006: Заместитель директора НИИ Трансплантологии и искусственных органов МЗ РФ
  • · 2006: Избран членом-корреспондентом Российской Академии Наук
  • · 2006-2011: Директор ФГУ «Всероссийский научно-исследовательский институт физической культуры и спорта» Министерства спорта, туризма и молодежной политики Российской Федерации
  • · 2011-2014: Заведующий лабораторией НИИ общей патологии и патофизиологии РАМН
  • · 2014-2017: Заведующий отделом трансляционной онкологии ФГБУ «НМИРЦ» Минздрава России
  • · 2017-2018: Ведущий научный сотрудник лаборатории биокатализа ФГБУН Институт биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова Российской академии наук (ИБХ РАН)
  • · 2018: с Заведующий кафедры клеточной биологии ФГАОУ ВО Национального исследовательского университета «Высшая школа экономики»
  • · Другие занимаемые должности
  • · Председатель экспертной комиссии по биологии и наукам о жизни Совета по грантам Президента РФ Министерства образования и науки РФ;
  • · Член экспертного совета по биотехнологии Министерства промышленности и торговли РФ;
  • · Заместитель председателя экспертного совета РФФИ по международным грантам.

Награды и поощрения

  • · Орден Дружбы народов (сентябрь 2024)
  • · Почетная грамота НИУ ВШЭ (март 2022)
  • · Благодарность Высшей школы экономики (декабрь 2021)
  • · Почетное звание "Заслуженный деятель науки Российской Федерации" (июнь 2018)
  • · Почетная грамота Российской Академии медицинских наук (июнь 2012)
  • · Надбавка за публикацию в журнале из Списка А (и приравненном к нему научном издании) (2024–2025, 2023–2024)
  • · Надбавка за публикацию в международном рецензируемом научном издании (2022–2023, 2021–2022, 2019–2021)
  • · Надбавка за регулярные публикации в международных рецензируемых научных изданиях (2025–2030)

Гранты и проекты

  • — · на соискание учёной степени кандидата наук

Конференции (1)

Показать все
  • · 2024: Седьмой онлайн-семинар по математическому моделированию в области иммунологии (Москва). Доклад: Моделирование динамики SARS-CoV-2 в клеточных линиях

Идентификаторы исследователя

Публикации (92)

scRNA-seq of preeclamptic trophoblasts identifies EBI3, COL17A1, miR-27a-5p, and miR-193b-5p as hypoxia markers: validation of neuradapt as a superior mimetic to cobalt chloride

2026 · ARTICLE · en

Background. Preeclampsia (PE) complicates 2–8% of pregnancies and involves placental hypoxia and HIF-pathway activation, especially in early-onset PE (eoPE). Chemical mimetics like cobalt(II) chloride (CoCl2) and oxyquinoline derivatives model trophoblast hypoxia in vitro, yet their fidelity in recapitulating PE gene profiles remains unclear. Integrating patient tissue analyses with experimental models may reveal common markers and validate physiologically relevant paradigms. Methods. We analyzed scRNA-seq data from 10 eoPE, 7 late-onset PE, and matched control placentas, identifying villous cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast (EVT). BeWo b30 cells were treated for 24 h with CoCl2 (300 µM) or the oxyquinoline derivative neuradapt (5 µM) to induce hypoxia. RNA-seq with qPCR validation and small RNA-seq quantified mRNA and microRNA changes; PROGENy inferred pathway activities. Results. scRNA-seq revealed highest hypoxia activation in eoPE, with EVT showing maximum activity. Nine genes were upregulated across all trophoblast types (EBI3, CST6, FN1, RFK, COL17A1, LDHA, PKP2, RPS4Y1, RPS26). In vitro, neuradapt induced more specific hypoxia responses than CoCl2 (1,284 vs. 3,032 differentially expressed genes). Critically, EBI3, FN1, and COL17A1 showed concordant upregulation in tissue and neuradapt-treated cells, whereas CoCl2 produced opposite patterns. MicroRNAs hsa-miR-27a-5p and hsa-miR-193b-5p were consistently elevated in both models; 3'-isoforms of hsa-miR-9-5p and hsa-miR-92b-3p were identified as hypoxia-associated. Conclusions. EBI3, COL17A1, miR-27a-5p, and miR-193b-5p emerge as trophoblast hypoxia markers. Neuradapt (a selective HIF-prolyl hydroxylase inhibitor) provides a more physiologically relevant in vitro model than CoCl2, recapitulating transcriptomic signatures observed in PE placentas. This integrated approach advances understanding of PE pathophysiology and therapeutic targeting.

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Targetome profile of hsa-miR-93-5p is resistant to isoform formation in prostate adenocarcinoma

2026 · ARTICLE · en

MicroRNAs (miRNAs) and their isoforms, known as isomiRs, are important regulators of tumorigenesis that act as post-transcriptional modulators of gene expression. Among these, 5’-isomiRs—generated through imprecise cleavage during miRNA biogenesis—exhibit altered seed regions compared to their canonical counterparts, potentially leading to distinct targetomes. Consequently, 5’-isomiRs may exert biological functions that differ substantially from those of the corresponding canonical miRNAs. Despite growing recognition of their potential significance, the functional roles of 5’-isomiRs remain largely uncharacterized for most miRNAs. In this study, we investigated the targetome divergence between canonical miRNAs and their 5’-isomiRs, focusing on hsa-miR-93-5p, a miRNA with a well-established oncogenic role in prostate adenocarcinoma. Target transcripts of the 5’-isomiRs were identified using a shRNA-based overexpression system. Bioinformatic analysis revealed a substantial overlap between the targets of the 5’-isomiRs and the canonical miRNA. This overlap was attributed to the co-occurrence of both canonical and shifted seed motifs within the same mRNA targets. Notably, hsa-miR-93-5p ranked among the top miRNAs with a relatively high number of targets transcripts containing both seed motifs, suggesting a unique dual-targeting capacity.

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Predicting Patient Outcomes with Gene-Expression Biomarkers from Colorectal Cancer Organoids and Cell Lines

2025 · ARTICLE · en

Colorectal cancer is characterized by an extremely high mortality rate, mainly caused by the high metastatic potential of this type of cancer. To date, chemotherapy remains the backbone of the treatment of metastatic colorectal cancer. Three main chemotherapeutic drugs used for the treatment of metastatic colorectal cancer are 5-fluorouracil, oxaliplatin and irinotecan which is metabolized to an active compound SN-38. The main goal of this study was to find the genes connected to the resistance to the aforementioned drugs and to construct a predictive gene expression-based classifier to separate responders and non-responders. In this study we used 7 established colorectal cancer organoids to conduct correlational analysis of the expression and drug resistance. We also included in the study publicly available datasets of colorectal cancer cell lines, thus combining two different in vitro models relevant to cancer research. The obtained results demonstrated that the expression of just a small group of genes consistently correlates with resistance to standard chemotherapeutic drugs in different datasets. Some of these genes have been previously connected to prognosis or response to anticancer drugs, but some of them were linked to drug resistance for the first time. Constructed gene expression signatures based on some of these genes enable the stratification of Stage II/III and Stage IV colorectal cancer patients and can be further validated in the clinic to improve the results of the treatment. Thus, by leveraging both organoids and cell lines, our study demonstrates the power of combining diverse experimental systems to uncover new prognostic markers and deepen our understanding of drug resistance in cancer.

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CD44 variant exons induce chemoresistance by modulating cell death pathways

2025 · ARTICLE · en

Cancer chemoresistance presents a challenge in oncology, often leading to treatment failure and disease progression. CD44, a multifunctional cell surface glycoprotein, has garnered attention for its involvement in various aspects of cancer biology. Through alternative splicing, CD44 can form isoforms with the inclusion of only standard exons, typical for normal tissue, or with the addition of variant exons, frequently expressed in cancer tissue and associated with chemoresistance. The functions of CD44 involved in regulation of cancer signaling pathways are being actively studied, and the significance of specific variant exons in modulating cell death pathways, central to the response of cancer cells to chemotherapy, begins to become apparent. This review provides a comprehensive analysis of the association of CD44 variant exons/total CD44 with clinical outcomes of patients undergoing chemotherapy. The role of CD44 variant exons v6, v9 and others with a significant effect on patient chemotherapy outcomes by means of key cellular death pathways such as apoptosis, ferroptosis and autophagy modulation is further identified, and their impact on drug resistance is highlighted. An overview of clinical trials aimed at targeting variant exon-containing isoforms is provided, and possible directions for further development of CD44-targeted therapeutic strategies are discussed.

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Autoantigenic peptide landscape of rheumatoid arthritis-associated HLA class II

2025 · ARTICLE · en

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by synovial joint damage and progressive loss of mobility. The human leukocyte antigen (HLA) class II alleles HLA-DRB1∗01:01 and HLA-DRB1∗04:01 are strongly linked to RA susceptibility. Several autoantigenic peptides were reported to bind to RA-associated HLA-II and trigger autoreactive CD4+ T cell response. Here, we propose a dual combinatorial approach to identify novel autoantigenic peptides presented by HLA-II. We generated a phage library containing fragments of human autoantigens to screen for peptide ligands binding RA-associated HLA-II. Concurrently, the HLA-II immunopeptidome of peripheral blood mononuclear cells from RA patients was analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). This approach led to the identification of a panel of RA-associated HLA-II peptide ligands, confirmed via in vitro binding assay. Identified autoantigens include fragments of annexin A11, endoplasmic reticulum chaperone BiP, calreticulin, and vimentin. Finally, we demonstrated that the annexin A11 fragment, in the complex with HLA-DRB1∗01:01, can activate CD4+ T cells from RA patients.

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Divergent ferroptotic pathways in breast cancer cells: IGFBP6-regulated mitochondrial lipid peroxidation under erastin and omega-3 DHA treatment

2025 · ARTICLE · en

Breast cancer remains a major challenge and new therapeutic approaches are needed for its treatment. Ferroptosis is considered a promising alternative cell death mechanism to eliminate resistant cancer cells. In previous works, we identified that lower IGFBP6 gene expression in tumor tissue corresponds to a worse prognosis for breast cancer patients and, at the same, time makes them more sensitive to ferroptosis. In this study, we further investigated the mechanism of ferroptosis induction in IGFBP6 knockdown and control MDA-MB-231 breast cancer cells by the canonical ferroptosis inducer erastin and omega-3 docosahexaenoic acid (DHA). Our results indicate that there is a significant overlap between the mechanisms of action of both of these molecules, as they regulate the same subset of genes, and their action can be inhibited by canonical ferroptosis inhibitors. On the other hand, we also observed significant differences between the effects of erastin and DHA. The most notable of these are the additional activation of apoptosis-related genes by DHA and its minor peroxidation of mitochondrial lipid membranes. Interestingly, our kinetic analysis of ferroptosis induction showed that IGFBP6 knockdown cells began to die earlier and could hardly be rescued from erastin-induced ferroptosis by mitochondrial antioxidant SkQ1, in contrast to control cells. Overall, our data suggest that the action of DHA is less dependent on mitochondrial membrane peroxidation during ferroptosis induction, and this molecule can be a promising candidate for the treatment of breast cancer, especially in the case of reduced IGFBP6 gene expression in cancer cells.

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Characterization of binding affinity changes of SARS-CoV-2 omicron variant peptides to population-specific HLA

2025 · ARTICLE · en

Background The evolution of SARS-CoV-2, particularly through new variants, presents significant global health challenges due to their potential for immune evasion and reduced vaccine effectiveness. This study aims to investigate the impact of mutations in the Spike protein of Omicron EG.5 and XBB.1.16 variants on the binding affinities of viral peptides to common human leukocyte antigen (HLA) class I and II alleles across Taiwanese, British, and Russian populations. Understanding these interactions is crucial for elucidating differences in immune responses and disease severity among diverse populations. Methods We updated the T-CoV portal to incorporate and analyze EG.5 and XBB.1.16 variants. Binding affinities between mutated Spike protein peptides and HLA class I and II alleles were predicted and compared across the three populations. Statistical analyses, including chi-squared tests, were conducted to assess the significance of binding affinity differences across the three populations and between HLA classes. Results Our findings revealed that mutations in the Spike protein had a more pronounced effect on HLA class II binding affinities than on HLA class I. While binding affinity profiles for HLA class I were largely consistent across populations, significant population-specific variations were observed for HLA class II alleles. Specifically, the British population exhibited lower proportions of tightly binding mutated peptides compared to the Taiwanese and Russian populations. Furthermore, substantial differences were identified in the binding affinity changes of mutated Spike peptides for HLA class II across Taiwanese, British, and Russian populations, as well as between the Omicron EG.5 and XBB.1.16 variants. Subsequent analyses revealed significant differences in the conservation and evolutionary trajectories of binding affinities between mutated Spike peptides and common HLA class II alleles, both between the EG.5 and XBB.1.16 variants and across the three populations for the XBB.1.16 variant. Conclusions In summary, Spike protein mutations in SARS-CoV-2 variants significantly influence immune responses by altering HLA-peptide interactions, with pronounced population-specific effects on HLA class II alleles. These findings underscore the critical role of HLA class II diversity in shaping immune responses and susceptibility to COVID-19. Integrating population-specific HLA profiles into vaccine development and public health strategies is essential for improving interventions against evolving SARS-CoV-2 variants.

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Interplay of integrins and selectins in metastasis

2025 · ARTICLE · en

Metastasis is a hallmark of malignancy and poses a formidable challenge for oncologists. This complex process begins when the primary malignant cells start to proliferate unlimitedly. Once the tumor reaches a certain size, cancer cells detach from the primary tumor mass and the basal lamina to which they are anchored, eventually invading nearby blood vessels. Within the bloodstream, these tumor cells have to survive and attach to the endothelium at distant sites. Cell-to-cell and cell-to-matrix interactions play an important role during these stages, in which integrins—a family of cell adhesion molecules (CAMs)—stand out as functionally centrally involved. Their expression on the tumor cell surface needs to be dynamically regulated throughout the process of metastasis. During the attachment phase to the endothelium, another group of CAMs, such as E-/P-selectins—primarily expressed on endothelial cells—may also play a critical role in certain malignancies. Additionally, the interplay between integrins and selectins may influence the tumor microenvironment. This review focuses on the role of integrins and their interplay with selectins in metastasis, emphasizing findings from in vivo studies.

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CD44 knockdown alters miRNA expression and their target genes in colon cancer

2025 · ARTICLE · en

Introduction: Metastasis formation poses a significant challenge to oncologists, as it severely limits the survival of colorectal cancer (CRC) patients. Recently, we demonstrated that CD44 promotes spontaneous distant metastasis in a CRC xenograft model. The depletion of CD44 was associated with reduction in hypoxia, EMT, as well as improved mitochondrial metabolism in primary tumor. Collectively, these effects decreased the metastatic potential of the CRC xenograft tumors under investigation. In this study we explore the molecular mechanisms by which CD44 knockdown (kd) leads to such substantial changes of tumor properties. Methods: Using miRNA-Seq data combined with bioinformatic analysis, we investigated the role of miRNA expression changes in the metastasis prevention observed with CD44 kd. Results: Among the differentially expressed miRNAs, three members of Let-7 family (let-7a-5p, let-7b-5p, and let-7c-5p), two isoforms of miR-203a (canonical miR-203a-3p and its +1 5’-isoform), miR-101-3p, miR-200b-3p|+1 5’-isoform, miR-125a-5p, and miR-185-5p were identified as potentially involved in regulating CD44-mediated metastasis. Gene set analysis of differentially expressed mRNA targets of these miRNAs, along with an examination of key regulators driving the observed changes in both mRNA and miRNA expression profiles, suggests that the CD44-STAT3-Let-7 miRNA axis as one of the most relevant in regulation of colon cancer metastasis via the CD44 receptor. Discussion: Our findings suggest a regulatory relationship between CD44, Let-7 miRNAs, and STAT3 in HT-29 tumors. Additionally, we propose the potential involvement of both isoforms of miR-203a (canonical and its +1 5’-isoform) in this regulatory network and suggest a role for miR-101-3p and miR-125a-5p in metastasis regulation through CD44 kd.

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Statistical Verification of Linear Classifiers

2025 · ARTICLE · en

We propose a homogeneity test closely related to the concept of linear separability between two samples. Using the test, one can answer the question of whether a linear classifier is merely ‘random’ or effectively captures differences between two classes. We focus on establishing upper bounds for the test's p-value when applied to two-dimensional samples. Specifically, for normally distributed samples, we experimentally demonstrate that the upper bound is highly accurate. Using this bound, we evaluate classifiers designed to detect ER-positive breast cancer recurrence based on gene pair expression. Our findings confirm the significance of IGFBP6 and ELOVL5 genes in this process.

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Курсы (6)