Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma

Guetta-Terrier, Charlotte; Karambizi, David; Akosman, Bedia; Chen, J; Kamle, Suchitra; Je, Fajardo; Fiser, András; Singh, RP; Sa, Toms; Lee, Chang-Min; Ja, Elias; Tapinos, Nikos

doi:10.1101/2021.10.01.462786

Cited by 4 publications

(4 citation statements)

References 51 publications

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“…CHI3L1 is prominently expressed in these tumors where it predicts radiation resistance and a poor prognosis (57). More recent investigations from our laboratory and others, also demonstrated that CHI3L1 drives mesenchymal differentiation of GBM stem cells (58) and that EGFR amplification is also a prominent feature of GBM. Based on these findings it is tempting to speculate that interactions such as the ones described above in NSCLC are operative in these other disorders.…”

Section: Discussionmentioning

confidence: 64%

Chitinase 3-like-1 (CHI3L1) in the Pathogenesis of Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer

Kamle,

Ma,

Schor

et al. 2023

Preprint

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Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In NSCLC, 10-20% of Caucasian patients and 30-50% of Asian patients have tumors with activating mutations in the Epidermal Growth Factor Receptor (EGFR). A high percentage of these patients exhibit favorable responses to treatment with tyrosine kinase inhibitors (TKI). Unfortunately, a majority of these patients develop therapeutic resistance with progression free survival lasting 9- 18 months. The mechanisms that underlie the tumorigenic effects of EGFR and the ability of NSCLC to develop resistance to TKI therapies, however, are poorly understood. Here we demonstrate that CHI3L1 is produced by EGFR activation of normal epithelial cells, transformed epithelial cells with wild type EGFR and cells with cancer-associated, activating EGFR mutations. We also demonstrate that CHI3L1 auto-induces itself and feeds back to stimulate EGFR and its ligands. Highly specific antibodies against CHI3L1 (anti-CHI3L1/FRG) and TKI, individually and in combination, abrogated the effects of EGFR activation on CHI3L1 and the ability of CHI3L1 to stimulate the EGFR axis. Anti-CHI3L1 also interacted with osimertinib to reverse TKI therapeutic resistance and induce tumor cell death and inhibit pulmonary metastasis while stimulating tumor suppressor genes including KEAP1. CHI3L1 is a downstream target of EGFR that feeds back to stimulate and activate the EGFR axis. Anti-CHI3L1 is an exciting potential therapeutic for EGFR mutant NSCLC, alone and in combination with osimertinib or other TKIs.

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Section: Discussionmentioning

confidence: 64%

Chitinase 3-like-1 (CHI3L1) in the Pathogenesis of Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer

Kamle,

Ma,

Schor

et al. 2023

Preprint

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“…Remarkably, neutralization of CHI3L1 is sufficient to restore iNKT cell activity, even in the presence of exogenous CHI3L1 supplementation. CHI3L1 can signal through CD44, one of its physiological receptors (34)(35)(36), which is upregulated in Pg-primed iNKT cells (Figure 3B). This signalling may act as an immune checkpoint to suppress iNKT cell activation via the PI3K/AKT pathway, a known repressor of STAT3 transcription (Figure 5F) (22,(37)(38)(39), but warrants further investigations.…”

Section: Discussionmentioning

confidence: 99%

Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion

Diaz Basabe,

Lattanzi,

Perillo

et al. 2023

Preprint

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The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). Porphyromonas gingivalis is a keystone oral pathogen associated with CRC. The oral pathobiont Fusobacterium nucleatum influences the anti-tumour functions of CRC-infiltrating iNKT cells. However, the impact of other oral bacteria, like P. gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumour microenvironment in CRC. Mechanistically, in vivo and in vitro experiments show that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery though increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing iNKT cells to upregulate CHI3L1, thus impairing iNKT cell cytotoxicity and promoting host tumour immune evasion.

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“…4h, Supplementary Fig. 4d), expressing CHI3L1, HGD and SLC4A10, which are linked to stemness and neuronal excitability [42][43][44]. Moreover, analysis of gene signatures linked to singlecell transcriptional states in GBM revealed that both OS21-8 and OS21-3 derived fractions share levels of the astrocytic-like program (Fig.…”

Section: Tertp Mutation and Single-cell Transcriptomic Heterogeneitymentioning

confidence: 95%

Cell sorting based on single nucleotide variation enables characterization of mutation-dependent transcriptome and chromatin states

Salatino,

Franco,

Romero-Toledo

et al. 2024

Preprint

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Single nucleotide variants (SNVs) contribute to cancer by altering the coding and the non-coding regions of the genome. Connecting SNVs to transcriptomic and epigenetic changes at the single-cell level remains challenging. To enable studies of rare cell populations harboring specific point mutations, we developed STAR-FACS, Specific-To-Allele PCR-FACS, to sort cells based on genomic allele alterations. We show that STAR-FACS can separate cells based on TERT promoter mutation status and is compatible with bulk and single-cell transcriptomic and epigenetic profiling. We demonstrate that glioblastoma cell lines derived from the same tumor but harboring distinct TERT promoter SNVs have different transcriptional programs.

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Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma

Cited by 4 publications

References 51 publications

Chitinase 3-like-1 (CHI3L1) in the Pathogenesis of Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer

Chitinase 3-like-1 (CHI3L1) in the Pathogenesis of Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer

Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion

Cell sorting based on single nucleotide variation enables characterization of mutation-dependent transcriptome and chromatin states

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