Biology subjects

Lomakin, A.

Publications and source records attributed to Lomakin, A..

6 recordsLinked to original sources

bioRxiv2026

Enforced ZFP281 expression delays breast cancer initiation and can provide lifelong protection against breast cancer metastasis

Breast cancer metastatic reactivation and its links to mammary development are largely unknown. Here, using conditional knockout and overexpression in normal and HER2+ mammary glands, we show that the dormancy regulator ZFP281 promotes branching and dissemination while suppressing growth, and its overexpression can even override HER2-driven cancer initiation. Notably, while ZFP281 does not limit HER2-driven early dissemination, it constrains DCC plasticity, confining cells to a dormant mesenchymal/hybrid-like state and effectively suppressing metastasis throughout the mouse lifespan. ZFP281 is induced by estrogen, progesterone, and glucocorticoid signaling, and RNA sequencing of early lesions revealed that it regulates glutathione metabolism and ferroptosis, potentially supporting fitness during dormancy, while repressing angiogenesis, Th17-like inflammation, innate immune genes, and pro-inflammatory programs that might otherwise trigger awakening. Integrating these findings with human data, we show that DCIS and IBC (invasive breast cancer) lesions that later relapse are selectively enriched for ZFP281-regulated M-like and dormancy signatures and, after pregnancy, depleted for a ZFP281-induced stress-autophagy module, indicating that erosion or imbalance of these programs marks lesions that seed DCCs with higher reactivation potential. We propose that ZFP281 acts as a hormone-regulated dormancy gatekeeper that uncouples dissemination from growth, enforcing a metabolically fit, angiogenesis-low, immune-evasive dormant state in breast DCCs, thereby shaping the timing of metastatic relapse and potentially exploitable for durable prevention of metastasis. STATEMENT OF SIGNIFICANCEZFP281, a hormone-regulated dormancy gatekeeper, uncouples dissemination from growth and constrains DCCs into long-term arrest, defining human gene signatures that distinguish dormancy-prone from awakening-prone lesions and predict breast cancer relapse dynamics.

cancer biology↗

bioRxiv2024

Integrated combinatorial functional genomics and spatial transcriptomics of tumors decodes genotype to phenotype relationships

Linking the complex genetic changes underlying cancer to relevant disease-phenotypes poses a challenge. Therefore, we present CHOCOLAT-G2P, a scalable approach that integrates multiplex in vivo functional genomics with spatial transcriptomics. By redeploying RNA-templated ligation probes of commercial spatial transcriptomics technology, we streamline mapping composite genetic alterations and transcriptome-wide phenotyping on the same tissue section on a single readout platform. Using this framework, we studied combinatorial effects of 8 perturbations that induce autochthonous mosaic liver tumors sampled from 256 genotypes. Interrogating 324 tumors across six [~]6x6 mm2 sections, we charted phenotypic landscapes of genotypically-defined tumor ecosystems, revealing zonation-associated hepatocellular carcinoma subclasses and associations between tumor subtypes and stromal-as well as immune-cell signatures. Further, we decoded epistasis within compound genotypes uncovering opposing roles of Vegfa and mutant Ctnnb1 to cholangiocarcinoma development. Thus, CHOCOLAT-G2P lays a foundation to decipher how combinations of alterations interact to reprogram tumor cells and their microenvironment within the holistic context of tissue and whole organisms. (https://chocolat-g2p.dkfz.de/).

cancer biology↗

bioRxiv2022

Advected percolation in the actomyosin cortex drives amoeboid cell motility

Spontaneous locomotion is a common feature of most metazoan cells, generally attributed to the fundamental properties of the actomyosin network. This force-producing machinery has been studied down to the most minute molecular details, especially in lamellipodium-driven migration. Nevertheless, how actomyosin networks work inside contraction-driven amoeboid cells still lacks unifying principles. Here, using stable motile blebs as a model amoeboid motile system, we image the dynamics of the actin cortex at the single filament level and reveal the co-existence of three phases of the actin network with distinct rheological properties. Physical modelling shows that these three phases organize spontaneously due to a rigidity percolation transition combined with an active advection of the percolated network. This spontaneous spatial organization of the mechanical properties of the actin network, which we propose to call advected percolation, constitutes a minimal and generic locomotion mechanism. It explains, down to the single actin filament level and up to the scale of the entire cell, how amoeboid cells can propel efficiently through complex 3D environments, a feature shared by immune and cancer cells.

biophysics↗

bioRxiv2021

Spatial genomics maps the structure, character and evolution of cancer clones

Subclonality is a universal feature of cancers yet how clones grow, are spatially organised, differ phenotypically or influence clinical outcome is unclear. To address this, we developed base specific in situ sequencing (BaSISS). In fixed tissues, transcripts harbouring clone-defining mutations are detected, converted into quantitative clone maps and characterised through multi-layered data integration. Applied to 8 samples from key stages of breast cancer progression BaSISS localised 1.42 million genotype informative transcripts across 4.9cm2 of tissue. Microscopic clonal topographies are shaped by resident tissue architectures. Distinct transcriptional, histological and immunological features distinguish coexistent genetic clones. Spatial lineage tracing temporally orders clone features associated with the emergence of aggressive clinical traits. These results highlight the pivotal role of spatial genomics in deciphering the mechanisms underlying cancer progression.

cancer biology↗

bioRxiv2020

Comprehensive mapping of tissue cell architecture via integrated single cell and spatial transcriptomics

The spatial organization of cell types in tissues fundamentally shapes cellular interactions and function, but the high-throughput spatial mapping of complex tissues remains a challenge. We present [c]ell2location, a principled and versatile Bayesian model that integrates single-cell and spatial transcriptomics to map cell types in situ in a comprehensive manner. We show that [c]ell2location outperforms existing tools in accuracy and comprehensiveness and we demonstrate its utility by mapping two complex tissues. In the mouse brain, we use a new paired single nucleus and spatial RNA-sequencing dataset to map dozens of cell types and identify tissue regions in an automated manner. We discover novel regional astrocyte subtypes including fine subpopulations in the thalamus and hypothalamus. In the human lymph node, we resolve spatially interlaced immune cell states and identify co-located groups of cells underlying tissue organisation. We spatially map a rare pre-germinal centre B-cell population and predict putative cellular interactions relevant to the interferon response. Collectively our results demonstrate how [c]ell2location can serve as a versatile first-line analysis tool to map tissue architectures in a high-throughput manner.

genomics↗

bioRxiv2019

The nucleus acts as a ruler tailoring cell responses to spatial constraints

The microscopic environment inside a metazoan organism is highly crowded. Whether individual cells can tailor their behavior to the limited space remains unclear. Here, we found that cells measure the degree of spatial confinement using their largest and stiffest organelle, the nucleus. Cell confinement below a resting nucleus size deforms the nucleus, which expands and stretches its envelope. This activates signaling to the actomyosin cortex via nuclear envelope stretch-sensitive proteins, upregulating cell contractility. We established that the tailored contractile response constitutes a nuclear ruler-based signaling pathway involved in migratory cell behaviors. Cells rely on the nuclear ruler to modulate the motive force enabling their passage through restrictive pores in complex three-dimensional (3D) environments, a process relevant to cancer cell invasion, immune responses and embryonic development. One Sentence SummaryNuclear envelope expansion above a threshold triggers a contractile cell response and thus acts as a ruler for the degree of cell deformation.

cell biology↗