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Mechanosensitive interactions of tumoroids with an engineered environment promote cell proliferation and enhance drug response detection

ABSTRACT: Despite remarkable advances in reproducing ever more sophisticated ex-vivo models, foundational challenges remain in standardizing and scaling up organoid culture. Here, we introduce a novel technology for high-throughput derivation and high-content analysis of tumoroids. This technology relied on microengineered tumoroid niches fabricated from PEG acrylate polymers by maskless photolithography to create a mechanically tunable microenvironment that is scalable and compatible with standard automated lab pipelines. We validated our innovative platform on patient-derived urothelial tumoroids and evaluated its use in high-end imaging approaches, including holotomography. Our results reveal that tumoroids dynamically interact and deform their synthetic environment, unravelling a mechanosensitive behavior of tumoroids depending on the features of their synthetic niche. Changing mechanical properties of microcavities modulated cell cycle dynamics and metabolism, as it affected their response to drugs, which highlights the critical role of mechanical stimuli in tumoroid development and future drug screening. Soft niches condition : M_N1/ M_N2/ M_N3/ M_N4 Stiff niches condition : S_N1/ S_N2/ S_N3/ S_N4 2D condition : 2D_N1/ 2D_N2/ 2D_N3/ 2D_N4

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Malignant Cell, Urinary Bladder Cancer Cell

DISEASE(S): Bladder Transitional Cell Carcinoma

SUBMITTER: Guillaume CHEVREUX

LAB HEAD: Kristine Schauer

PROVIDER: PXD058623 | Pride | 2025-07-24

REPOSITORIES: Pride

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			Action	DRS
	2406001_2D_N1_S1-B4_1_11548.d.refined.mgf	Mgf
	2406001_2D_N1_S1-B4_1_11548.d.zip	Other
	2406001_2D_N2_S1-B5_1_11549.d.refined.mgf	Mgf
	2406001_2D_N2_S1-B5_1_11549.d.zip	Other
	2406001_2D_N3_S1-B6_1_11550.d.refined.mgf	Mgf

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Project description:Background & Aims: Cholangiocarcinomas (CCAs), heterogeneous biliary tumors with dismal prognosis, lack accurate early-diagnostic methods, especially important for individuals at high-risk (i.e., primary sclerosing cholangitis (PSC)). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). Methods: EVs from patients with isolated PSC (n=45), concomitant PSC-CCA (n=42), PSC who developed CCA during follow-up (PSC to CCA; n=25), CCAs from non-PSC etiology (n=56), hepatocellular carcinoma (n=34) and healthy individuals (n=55) were characterized by mass-spectrometry. Diagnostic biomarkers of PSC-CCA, non-PSC CCA or CCAs regardless etiology (pan-CCAs) were defined, and their expression was evaluated in human organs/tissues and within CCA tumors at single-cell level. Prognostic EV-biomarkers for CCA were investigated. Results: High-throughput proteomics identified candidate diagnostic biomarkers for PSC-CCA, non-PSC CCA or pan-CCA, as well as and for differential diagnosis of intrahepatic CCA and HCC, that were cross-validated by ELISA using total serum. Machine learning logit modelling disclosed CRP/FRIL/Fibrinogen algorithm with diagnostic value for early-stage PSC-CCA vs isolated PSC (AUC=0.944; OR=82.0), overpowering CA19-9 (AUC=0.735; OR=9.3). An algorithm combining CRP/VWF/PIGR/ /Fibrinogen allowed the diagnosis of early-stage non-PSC CCAs compared to healthy individuals (AUC=0.999; OR=1115). Noteworthy, levels of Fibrinogen/CRP/PIGR/FRIL showed predictive capacity for CCA development in patients with PSC before clinical evidences of malignancy. Multi-organ transcriptomic analysis revealed that serum EV-biomarkers were mostly expressed in hepatobiliary tissues, and scRNA-seq and immunofluorescence analysis of CCA tumors showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EVprognostic biomarkers independent to clinical features, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively or positively to patients’ survival, respectively. Conclusions: Serum EVs contain protein biomarkers for the prediction, early diagnosis and prognosis estimation of CCA, representing a novel tumor cell-derived liquid biopsy for personalized medicine.

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Mechanosensitive interactions of tumoroids with an engineered environment promote cell proliferation and enhance drug response detection

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