https://www.science.org/doi/10.1126/science.adz7928
Sadly this is behind a paywall. I think it is particularly important as it goes towards confirming Thomas Seyfrieds view that the macrophages create metatstasis by taking the duff mitochondria from the tumour and spreading them.
Editor’s summary
Metastasis refers to the spread of cancer cells beyond the primary tumor site to distant parts of the body. The process of how tumors initiate metastatic outgrowth and survive in other organs is not clear. Sun et al. used spatiotemporal multiomics to profile cellular interactions in liver cancer. Using experimental models and human samples, liver cancer cells were tracked from their initial arrival in the lungs throughout the metastatic trajectory. A rare subpopulation of transient, quiescent Phgdh high-expressing tumor cells were identified that survived by establishing an immunosuppressive niche to evade clearance by the immune system. Before metastatic outgrowth, Cx3cr1 high interstitial macrophages accumulated within the niche, creating a permissive microenvironment for cancer expansion. Disrupting these processes restored immune surveillance and suppressed metastasis. —Priscilla N. Kelly
Structured Abstract
INTRODUCTION
Metastasis is the primary cause of cancer-related mortality, yet the earliest event of colonization, where the fate of disseminated tumor cells (DTCs) is decided, remains largely unknown. Although most DTCs are eliminated on arrival in secondary organs, a resilient minority survives to initiate lethal outgrowth. Capturing these rare, transient populations in clinical specimens is technically challenging, and precise molecular mechanisms that allow DTCs to evade immune surveillance and remodel their local environment are currently unclear.
RATIONALE
To resolve the cellular and molecular dynamics of early metastatic seeding, we constructed a comprehensive multimodal spatiotemporal atlas. By integrating high-resolution spatial transcriptomics (Stereo-seq), single-cell RNA sequencing, and chromatin accessibility profiling, we tracked DTCs and their evolving microenvironment across nine sequential stages of lung colonization in mouse models. These findings were further validated against human metastatic specimens. This approach allowed us to map the coevolution of tumor states and host immune niches with high-level resolution.
RESULTS
Our analysis reveals that metastatic colonization is not a stochastic event but a highly coordinated spatiotemporal evolution of the tumor ecosystem. After a massive innate immune clearance, primarily by neutrophils and natural killer (NK) cells, a rare subpopulation of DTCs survived by entering a transient, quiescent Phgdh high state. These cells established an immune-scarce niche. Lineage tracing confirmed that the majority of lethal macrometastases originate from ancestors that transiently passed through the Phgdh high state. Mechanistically, alveolar type 2 (AT2) cells transiently enriched within the niche of surviving DTCs actively induce the Phgdh high state. Elevated PHGDH activity fuels one-carbon flux to increase S-adenosylmethionine (SAM) levels. This metabolic shift drives histone H3K27 trimethylation (H3K27me3)–mediated epigenetic silencing of proinflammatory chemokine genes (e.g., Ccl2 and Cxcl10). Critically, pharmacological or genetic perturbation of this axis restored chemokine expression and reengaged immune surveillance, significantly suppressing metastatic outgrowth. Before macrometastatic expansion, the DTC niche undergoes a second remodeling event marked by accumulation of Cx3cr1 high interstitial macrophages. The macrophages recruited immunosuppressive cells (T regulatory cells, neutrophils, and alveolar macrophages) and provided growth signals through the IGF1-IGF1R axis that trigger the transition of DTCs from quiescence to rapid proliferation. Depletion of CX3CR1high interstitial macrophages significantly reduced metastatic burden.
CONCLUSION
Metastatic colonization proceeds through two temporally ordered “niche-shaping” events: an initial epigenetically driven Phgdh high DTC state that silences the local immune milieu followed by Cx3cr1 high macrophage-mediated niche remodeling that supports outgrowth. Our findings define a comprehensive spatiotemporal map of the tumor ecosystem across the entire continuum of seeding and outgrowth. By identifying these transient cellular states and niches as temporally distinct vulnerabilities, we provide a conceptual roadmap for intercepting metastatic colonization and outgrowth.
Spatiotemporal multiomics reveals tumor ecosystem dynamics throughout metastatic progression.
Tumor cells disseminating to the lung first enter a neutrophil-enriched niche and undergo innate immune clearance. Rare survivors then persist in an immune-scarce niche marked by elevated Phgdh and H3K27me3 and reduced chemokine expression, maintaining quiescence. Later, tumor-derived CX3CL1 recruits CX3CR1high interstitial macrophages to remodel the niche and trigger metastatic reactivation. An adaptive immune-inflamed niche then emerges, accompanied by enhanced tumor proliferation and immune evasion, ultimately leading to macrometastatic outgrowth. DC, dendritic cell.
Abstract
The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdh high DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1 high interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.