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Liver-metastases restrict IL18-driven γδ T cell activity and immunotherapy responsiveness in colorectal cancer

ABSTRACT: To see how the secretome changes upon challenging organoids with immune pressure, we wanted to perform secretomics on CRC MSI organoids +- stimulation with IFNy. Secretomics was performed using a previously published metabolic labeling method based on threonine-derived non-canonical amino acid tagging (THRONCAT) [1].

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell Line Cell, Colorectal Cancer Cell

DISEASE(S): Colorectal Cancer

SUBMITTER: Onno Bleijerveld

LAB HEAD: Onno Bleijerveld

PROVIDER: PXD071538 | Pride | 2025-12-09

REPOSITORIES: Pride

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			Action	DRS
	20241223_Astral_AUR325075C18TS_DIA_30SPD_Project_998_s17.raw	Raw
	20241223_Astral_AUR325075C18TS_DIA_30SPD_Project_998_s18.raw	Raw
	20241223_Astral_AUR325075C18TS_DIA_30SPD_Project_998_s19.raw	Raw
	20241223_Astral_AUR325075C18TS_DIA_30SPD_Project_998_s20.raw	Raw
	20241223_Astral_AUR325075C18TS_DIA_30SPD_Project_998_s21.raw	Raw

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Project description:We developed a human cerebral organoid model derived from induced pluripotent stem cells (iPSCs) with targeted genome editing to abolish protein expression of the Contactin Associated Protein-like 2 (CNTNAP2) autism spectrum disorder (ASD) risk gene, mimicking loss-of-function mutations seen in patients. CNTNAP2-/- cerebral organoids displayed accelerated cell cycle, ventricular zone disorganisation and increased cortical folding. Proteomic analysis revealed disruptions in glutamatergic/GABAergic synaptic pathways and neurodevelopment, highlighting increased protein expression of corticogenesis and neurodevelopment-related genes such as Forkhead box protein G1 (FOXG1) and Paired box 6 (PAX6). Transcriptomic analysis revealed differentially expressed genes (DEG) belonging to inhibitory neuron-related gene networks. Interestingly, there was a weak correlation between the transcriptomic and proteomic data, suggesting nuanced translational control mechanisms. Along these lines we find upregulated Protein Kinase B (Akt)/mechanistic target of rapamycin (mTOR) signalling in CNTNAP2-/- organoids. Spatial transcriptomics analysis of CNTNAP2-/- ventricular zones demonstrated pervasive changes in gene expression, particularly in PAX6- cells, implicating upregulation of cell cycle regulation pathways, synaptic and glutamatergic/GABAergic pathways. We noted a significant overlap of all omics datasets with idiopathic ASD (macrocephaly) iPSC-derived telencephalic organoids DEG, where FOXG1 was upregulated, along with aberrant expression of Glutamate decarboxylase 1 (GAD1) and T-Box Brain Transcription Factor 1 (TBR1), suggesting altered GABAergic/glutamatergic neuron development. These findings potentially highlight a shared mechanism in the early cortical development of various forms of ASD, further elucidate the role of CNTNAP2 in ASD pathophysiology and cortical development and pave the way for targeted therapies using cerebral organoids as preclinical models.

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Liver-metastases restrict IL18-driven γδ T cell activity and immunotherapy responsiveness in colorectal cancer

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