Biology subjects

Ratliff, M.

Publications and source records attributed to Ratliff, M..

3 recordsLinked to original sources

bioRxiv2026

Collective cancer cell calcium activity drives brain metastasis

Communication in multicellular networks is a cancer-intrinsic neural feature and crucial for primary brain tumor growth and resistance, but it is unclear whether brain metastases (BrM), the most common and deadliest brain malignancy, are also driven by communicating cancer networks. Using intravital two-photon microscopy in awake mice, clinical specimens, and Ca2+ integrators, we demonstrate that brain-colonizing breast and lung cancer and melanoma cells display gap-junction-dependent, coordinated Ca2+ activity in multicellular, cancer-cell intrinsic networks, which drives their proliferation. Mechanistically, Ca2+ oscillations induce transcription of immediate early genes, adoption of a neuronal expression profile, and cell cycle progression. While many of those features are enriched in BrM, all investigated cancer cell lines showed collective Ca2+ activity. Therapeutically, blocking Ca2+ activity with gap junction inhibitors reduces BrM burden in mouse models. Here we show communicating cancer cell syncytia as drivers of BrM growth, pointing to a targetable pathomechanism, and potentially a new pan-cancer hallmark. Graphical AbstractIn brief Brain metastases form gap-junction-coupled networks exhibiting spontaneous, coordinated Ca2+ activity linked to immediate early gene activation, neuronal gene programs, and cell cycle progression. Disrupting Ca2+ network communication with gap junction inhibitors induces cell cycle arrest and reduces brain metastatic burden in vivo. O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/723715v1_ufig1.gif" ALT="Figure 1"> View larger version (88K): org.highwire.dtl.DTLVardef@1130ea0org.highwire.dtl.DTLVardef@254dcdorg.highwire.dtl.DTLVardef@117021forg.highwire.dtl.DTLVardef@18c4f1e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBrain metastases display collective Ca2+ activity in gap-junction-coupled networks C_LIO_LICa2+ co-activity is conserved across cancers but enriched in brain metastasis C_LIO_LICa2+ oscillations robustly induce neuronal gene programs and cell cycle progression C_LIO_LIGap junction inhibition reduces brain metastasis burden in mice C_LI

cancer biology↗

bioRxiv2022

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of nuclear factor of activated T cells (Nfat)2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors. Highlights- MHCII on intratumoral blood-borne myeloid cells is required for sustained anti-glioma T cell response - Loss of myeloid MHCII drives dysfunction of CD8+ T cells by activating TOX - Tox expression is induced by osteopontin-triggered chronic NFAT2 signaling in tumor-reactive CD8+ T cells - steopontin production is restricted upon intratumoral T helper cell activation via MHCII - MHCII expression on tumor-infiltrating bbm correlates with osteopontin expression and cytotoxic T cell dysfunction in human glioblastoma tissue O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/495502v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1fbedc7org.highwire.dtl.DTLVardef@b7dc3aorg.highwire.dtl.DTLVardef@db7fe6org.highwire.dtl.DTLVardef@aa06b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Integrated phospho-proteogenomic and single-cell transcriptomic analysis of meningiomas establishes robust subtyping and reveals subtype-specific immune invasion

Meningiomas are the most frequent primary intracranial tumors. They can follow a wide clinical spectrum from benign to highly aggressive clinical course. No specific therapy exists for refractory cases or cases not amenable to resection and radiotherapy. Identification of risk of recurrence and malignant transformation for the individual patients is challenging. However, promising molecular markers and prognostic subgrouping by DNA methylation are emerging. Still, the biological underpinnings of these diagnostic subgroups are elusive, and, consequently, no novel therapeutic options arise thereof. Here we establish robust subgroups across the full landscape of meningiomas, consistent through DNA methylation, mutations, the transcriptomic, proteomic and phospho-proteomic level. Pronounced proliferative stress and DNA damage repair signals in malignant cells and in clusters exclusive to recurrent tumors are in line with their higher mitotic activity, but also provide an explanation for the accumulation of genomic instability in anaplastic meningiomas. Although homozygous deletion of CDKN2A/B is a diagnostic marker of high-grade meningioma, the expression of its gene product increased from low to non-deleted high-grade cases. Differences between subgroups in lymphocyte and myeloid cell infiltration, representing a majority of tumor mass in low-grade NF2 tumors, could be assigned to cluster-specific interaction with tumor cells. Activation to a more proinflammatory phenotype and decreased infiltration of myeloid cells in high-grade cases correlated with lower expression of CSF1, located on chromosome arm 1p, whose deletion is known as prognostic marker, with no proposed mechanism before. Our results demonstrate a robust molecular subclassification of a tumor type across multiple layers, provide insight into heterogeneous growth dynamics despite shared pathognomonic mutations, and highlight immune infiltration modulation as a novel target for meningioma therapy.

genomics↗