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L1CAM generates SOX2+ metastatic progenitors through planar cell polarity signaling in lung adenocarcinoma

ABSTRACT: Lung adenocarcinoma (LUAD) is a leading cause of cancer-related deaths worldwide, with most fatalities attributed to metastasis. A primitive SOX2+ progenitor state, rare in primary tumors, becomes prominent in LUAD metastatic lesions and exhibits metastasis-initiating capacity. The signals that determine the emergence of SOX2+ progenitors are unknown. We report that the cell adhesion molecule L1CAM, a marker of metastasis-initiating regenerative progenitors, plays a crucial role in the emergence of LUAD SOX2+ progenitors. Mechanistically, L1CAM induces the planar cell polarity (PCP) complex to activate c-Jun, which in turn interacts with the chromodomain helicase CHD1 to drive Sox2 transcription and generate metastasis-initiating regenerative progenitors. Treatment with an L1CAM antibody drug conjugate (ADC) effectively eliminates these LUAD cells and eradicates patient-derived xenograft metastases. Our findings identify L1CAM/PCP signaling as a driver of the SOX2+ LUAD metastatic progenitor state and provide an approach to treating metastasis by targeting L1CAM+ LUAD progenitors.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE284443 | GEO | 2026/04/16

REPOSITORIES: GEO

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Project description:A detailed understanding of intestinal stem cell (ISC) self-renewal and differentiation is required for better treatment options for a variety of chronic intestinal diseases, however, current models of ISC lineage hierarchy and segregation are still under debate. Here we report the identification of Lgr5+ ISCs that express Flattop (Fltp), a Wnt/planar cell polarity (PCP) reporter and effector gene. Functional analysis and lineage tracing revealed that Wnt/PCP-activated Fltp+ ISCs are primed towards either the enteroendocrine or Paneth cell lineage in vivo, while retaining self-renewal and multi-lineage capacity in vitro. Surprisingly, canonical Wnt/beta-catenin- and non-canonical Wnt/PCP-activated Lgr5+ ISCs are indistinguishable by the expression of stem-cell signature or secretory lineage-specifying genes, suggesting that lineage priming and cell-cycle exit is triggered at the post-transcriptional level by polarity cues and a switch of canonical to non-canonical Wnt signalling. Pseudotemporal ordering of targeted single-cell gene expression data allowed us to delineate the ISC differentiation path into enteroendocrine and Paneth cells. Strikingly, both lineages are directly recruited from ISCs via unipotent transition states, excluding the existence of formerly predicted bi- or multipotent secretory progenitors. Transitory cells that mature into Paneth cells are defined by label-retention and co-expression of stem cell and secretory lineage genes, indicating that these cells are the previously described Lgr5+ label-retaining cells (LRCs). Taken together, we identified the Wnt/PCP pathway as a new niche signal and polarity cue regulating stem cell fate. Active Wnt/PCP signalling represents one of the earliest events in ISC lineage priming towards the Paneth and enteroendocrine cell fate, preceding lateral inhibition and expression of secretory lineage-specifying genes. Thus, our findings provide a better understanding of the niche signals and redefine the mechanisms underlying ISC lineage hierarchy and segregation. Here we establish the Wnt/Planar cell polarity (PCP) gene Flattop (Fltp) as a unique marker for intestinal LRCs and their distinct secretory fate. We show that Fltp+ cells are characterized by a combined stem cell and secretory gene signature. A subset of Fltp+ cells is classified by label-retention and predominantly locates at position +4, indicative of quiescent stem cells. Strikingly, Fltp+ LRCs are specified by Wnt/PCP signaling in contrast to actively cycling stem cells that rely on the canonical Wnt/β-catenin pathway. In mice with disturbed Wnt/PCP signaling, the differentiation of enteroendocrine cells from LRCs is impaired. These findings establish Fltp as a novel marker for intestinal LRCs and implicate Wnt/PCP signaling in cell-cycle exit and commitment of ISCs to the secretory lineage. Taken together, we not only provide a marker to study LRCs in homeostatic and diseased conditions, but also identify the Wnt/PCP signaling pathway as a therapeutic target for colorectal cancer and metabolic disease.

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L1CAM generates SOX2+ metastatic progenitors through planar cell polarity signaling in lung adenocarcinoma

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