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Skamagki, M.

Publications and source records attributed to Skamagki, M..

4 recordsLinked to original sources

Discovering Latent Scientific Concepts through Discrete Representation Learning

Scientific imaging is undergoing a fundamental transformation. Advances in multiplex immunofluorescence, computational pathology, and electron microscopy now enable observation of biological and physical systems at unprecedented spatial resolution. Rather than simply classifying known objects, these data offer the opportunity to discover previously unknown organizational principles. However, scientific image datasets are typically highly curated, information-rich, and limited in size, making reliable representation learning particularly challenging. We show that standard continuous self-supervised adaptation can become unstable in this regime, allowing teacher representations to drift and degrading downstream transfer. We introduce Kodiak, a discrete representation learning architecture that discovers latent scientific concepts through Sinkhorn-balanced codebook assignments. Instead of learning unconstrained continuous embeddings, Kodiak constructs a reusable vocabulary of discrete concepts that provides stable supervision for both masked-patch prediction and cross-view representation learning within a single-stage framework. Across five scientific imaging domains, including multiplex immunofluorescence for pancreatic cancer pathology and scanning electron microscopy, Kodiak consistently improves representation quality under both continued foundation-model adaptation and training from scratch. Beyond improved classification and transfer,the learned concepts are interpretable, reusable, and produce spatially coherent concept maps that support applications such as cell phenotyping, segmentation-free patch phenotyping, spatial niche discovery, tissue organization, and materials characterization. We view Kodiak as the representation-learning engine of our foundation model for spatial biology. More broadly, our results suggest that discrete representation learning provides a principled foundation for discovering reusable latent scientific concepts that can accelerate scientific interpretation across imaging domains.

cancer biology↗

Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer

Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune-checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.

cancer biology↗

Genetic mechanisms of resistance to targeted KRAS inhibition

KRAS mutations are among the most prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), yet the mechanisms of therapeutic resistance to KRAS inhibitors in these cancers remains poorly understood. Here, we deploy high-throughput CRISPR base editing screens to systematically map resistance mutations to three mechanistically distinct KRAS-targeted therapies, including KRAS-G12C(OFF) inhibitor (adagrasib), RAS(ON) G12C-selective tri-complex inhibitor (RMC-4998), and RAS(ON) multi-selective tri-complex inhibitor (RMC-7977). Using both a saturation Kras tiling approach and cancer-associated mutation library, we identify common and compound-selective second-site resistance mutations in Kras, as well as gain-of-function and loss-of-function variants across cancer-associated genes that rewire signaling networks in a context-dependent manner. Notably, we identify a recurrent missense mutation in capicua (Cic), that promotes resistance to RMC-7977 in vitro and in vivo. Moreover, we show that targeting NF{kappa}B signaling in CIC-mutant cells can resensitize them to RAS pathway inhibition and overcome resistance.

cancer biology↗

Aging-dependent dysregulation of EXOSC2 is maintained in cancer as a dependency

Reprogramming of aged donor tissue cells into induced pluripotent stem cells (A-iPSC) preserved the epigenetic memory of aged-donor tissue, defined as genomic instability and poor tissue differentiation in our previous study. The unbalanced expression of RNA exosome subunits affects the RNA degradation complex function and is associated with geriatric diseases including premature aging and cancer progression. We hypothesized that the age-dependent progressive subtle dysregulation of EXOSC2 (exosome component 2) causes the aging traits (abnormal cell cycle and poor tissue differentiation). We used embryonic stem cells as a tool to study EXOSC2 function as the aging trait epigenetic memory determined in A-iPSC because these aging traits could not be studied in senesced aged cells or immortalized cancer cells. We found that the regulatory subunit of PP2A phosphatase, PPP2R5E, is a key target of EXOSC2 and this regulation is preserved in stem cells and cancer.

cell biology↗