bims-metorg 2025-12-21 papers

Issue of 2025–12–21
four papers selected by
Bruna Martins Garcia, CABIMER

Nat Methods. 2025 Dec 17.

Inferring cancer type-specific patterns of metastatic spread using Metient.

Divya Koyyalagunta, Karuna Ganesh, Quaid Morris.

Cancers differ in how they spread. These routes of metastatic dissemination can be reconstructed from tumor sequencing data, but current reconstruction methods scale poorly or rely on assumptions that do not reflect known biology. Metient overcomes these limitations using gradient-based, multiobjective optimization to generate multiple hypotheses of metastatic spread that are rescored using independent genetic distance and organotropism data. Unlike current methods, Metient can be used with both clinical sequencing data and barcode-based lineage tracing in preclinical models. Here, applied to data from 167 patients and 479 tumors, Metient identifies distinct trends of metastatic dissemination in melanoma, high-risk neuroblastoma and non-small cell lung cancer. Its reconstructions usually match expert analyses but Metient often finds other plausible migration histories, ultimately positing more polyclonal and metastasis-to-metastasis seeding than previously reported. Metient's reconstructions thus challenge existing assumptions about metastatic dissemination and offer insights into cancer type-specific patterns of metastatic spread.

DOI: https://doi.org/10.1038/s41592-025-02924-8

Cell Biol Int. 2026 Jan;50(1): e70110

Unravelling Mechanisms of Cancer Cells' Tropism for Metastasis: A Key to Improved Cancer Therapies.

Sumit Mallick, Jahnvi Hora, T K Varun, Sudheer Shenoy P, Bipasha Bose.

Selective migration of tumors to particular organs, referred to as organ tropism, is not arbitrary but guided by intricate molecular interactions and a complex network of various secretory molecules. This site-specific migration is modulated by molecular crosstalk, where cytokines and other effectors help tumor cells adapt to and colonize a new organ by reshaping their epigenetics. It is well established that breast and colorectal cancers, for instance, can epigenetically modify themselves to show a preference for the brain, bones, lungs, and liver but the key modulators are still elusive. Here, we have discussed the key mechanisms, including the critical interacting molecules, cytokines, and pathways that drive this site-specific tropism-based colonization. By synthesizing current knowledge, we highlight central players in this process and discuss their potential as therapeutic targets to inhibit metastasis and improve patient outcomes.

Keywords: breast cancer; colorectal cancer; targeted therapy; tumor microenvironment; tumor tropism

DOI: https://doi.org/10.1002/cbin.70110

Front Immunol. 2025 ;16 1665099

The significance of trained immunity in cancer.

Junxing Qu, Xinya Guo, Xinru Wang, Huiwen Meng, Peizhi Li, Zhiheng Sun.

Trained immunity (TI) represented a unique state of innate immune activation, characterized primarily by persistent epigenetic modifications in immune cells. This phenomenon was first observed during pathogen infections and vaccinations, where it manifested as enhanced defensive responses in innate immune effector cells-such as those of the mononuclear phagocyte system and natural killer cells-upon re-stimulation. Cancer was a disease with complex mechanisms, marked by the loss of normal growth regulation in cells due to genetic mutations or epigenetic dysregulation, leading to abnormal proliferation and dissemination. With hundreds of subtypes, cancer could arise in virtually any human tissue or organ. The primary cause of cancer-related mortality was metastasis, which referred to the spread of cancer cells from their original site to distant organs and accounted for approximately 90% of cancer deaths worldwide. The induction of TI involved multiple immune components including myeloid cells, natural killer cells, pattern recognition receptors, and various cytokines. Notably, the enhanced response observed during secondary stimulation remained non-specific to particular pathogens. Compared to conventional therapeutic approaches, TI demonstrated superior systemic immune activation. Simple pharmacological stimuli such as β-glucan or Bacillus Calmette-Guérin (BCG) not only triggered innate immune responses but also conferred benefits to adaptive immunity, resulting in more rapid immune activation and enhanced efficacy. TI enhanced the capacity of immune cells to recognize and eliminate cancer cells, playing a critical role in countering metastasis. In this review, we summarized existing knowledge in the field, focusing on the mechanisms underlying TI induction and its significance in combating cancer.

Keywords: colorectal cancer; gastric cancer; liver cancer; lung cancer; trained immunity

DOI: https://doi.org/10.3389/fimmu.2025.1665099

bioRxiv. 2025 Nov 25. pii: 2025.09.08.674915. [Epub ahead of print]

Serial Imaging of Tumour and microEnvironment (SITE) platform for live-cell ex vivo modelling of primary and metastatic cancer dynamics.

Vaibhav Murthy, Rawan Makkawi, Francis Anderson, Carol Halsey, Elise Manalo-Hall, Sanjay Srikanth, Gabriella Tangkilisan, Ting Zheng, James McGann, Marc R Birtwistle, Jeremy Copperman, Alexander E Davies.

Understanding cancer initiation and progression is extremely challenging, in part due to experimental limitations in measuring and interpreting key signalling and tumour-microenvironment (TME) interactions that determine changes in cell and tissue behaviours over time. Here we developed SITE (Serial Imaging of Tumour and microEnvironment), a spatially-and temporally integrated, modular, ex vivo platform enabling quantitative analysis of TME interaction dynamics, signalling, and cell fate at single cell and tissue scales. Applied to modelling primary and lung metastatic breast cancer, SITE revealed tissue-specific TME interactions and ERK signalling patterns linked to distinct single-cell behaviours. We found that the earliest steps in tumour establishment and metastatic seeding involved active cell protrusion and the establishment of a multicellular niche interfacing tumour and host. Experimental and mathematical modelling showed that ERK signalling was co-influenced by these interactions, where cancer cluster formation increased signalling via the establishment of local signalling circuits. Disruption of these signalling circuits led to tissue-specific impacts on cancer intrinsic and TME interaction dynamics. Here, we modelled breast cancer as a test case, demonstrating the broad utility of SITE for quantitative exploration of TME interaction dynamics‒ closing a significant gap in experimental capabilities between in vivo models and in vitro systems.

DOI: https://doi.org/10.1101/2025.09.08.674915