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A co-culture system of macrophages with breast cancer tumoroids to study cell interactions and therapeutic responses

ABSTRACT: 3D tumoroids have revolutionized in vitro/ex vivo cancer biology by recapitulating the complex diversity of tumors. While tumoroid provide new insights into cancer development and treatment response, several limitations remain. The tumor microenvironment, especially the immune system, strongly influences tumor development. Absence of immune cells in tumoroids may yield flawed conclusions. Macrophages, key players in tumor progression, pose integration challenges into tumoroid. In this study, we established three optimized and standardized methods for co-culturing human macrophages with breast cancer tumoroids: a semi-liquid model and two matrix-embedded models tailored for specific applications. Optimizing culture conditions, we tracked interactions and macrophage infiltration using flow cytometry and light sheet microscopy. Macrophages not only influenced tumoroid molecular profiles but also chemotherapy response. This underscores the importance of increasing the complexity of current 3D models to more accurately reflect in vivo conditions. The three models have different application and can be used in various ways.

INSTRUMENT(S): timsTOF fleX

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Malignant Cell, Primary Cell, Cell Culture, Macrophage

DISEASE(S): Breast Cancer

SUBMITTER: Antonella Raffo Romero

LAB HEAD: Michel Salzet

PROVIDER: PXD052016 | Pride | 2024-05-31

REPOSITORIES: Pride

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Project description:Ovarian cancer (OC) ranks among the deadliest cancers in women. Lack of symptoms, rapid spread of metastases and common chemoresistance contribute to unfortunate fate of majority of OC patients, especially those having high-grade serous carcinoma of the ovary, fallopian tube and peritoneum (HGSC), the most common type of OC. Many HGSC patients have excess fluid in the peritoneum at the stage of diagnosis called ascites. Ascites is basically a tumor microenvironment (TME) in the liquid form containing various cells, proteins and also extracellular vesicles (EVs). EVs are small membrane-bound particles that convey proteins, lipids and nucleic acids between cells and their cargo reflects the cell of origin. EVs play important role in cancerogenesis and hold great promise as disease biomarkers as well as potential therapeutic targets. Small size and polydispersity of EVs bring various challenges to their isolation and characterization, including method-dependent enrichment of different EV subtypes as well as contaminants. We isolated EVs from ascites of 11 patients by two different methods (ultracentrifugation coupled to sucrose cushion and size-exclusion chromatography, qEV column) and analyzed them by mass spectrometry. We identified core ascitic EV proteins present in all patients that contain typical EV markers and are devoid of method-dependent contaminants. To cover interpatient heterogeneity, we expanded this “core proteome” with proteins found in majority of patients. Next, we compared them with proteins of EVs from related control fluids and uncovered proteins present only on EVs from HGSC patients. We believe this list of proteins contain both important players of HGSC progression as well as potential biomarkers. Using single cell RNA sequencing data, we mapped the origin of EVs to different types of cells present in malignant ascites. Our results suggest that EVs in ascites do not come predominantly from tumor cells, but rather from variety of non-malignant cell types including cancer-associated fibroblasts and tumor-associated macrophages, which presence in ascites was confirmed by flow cytometry. This emphasizes the recently appreciated role of TME in the progression of HGSC. To conclude, this is the first study attempting to link EV composition to the cell types producing it. As such it opens numerous avenues both for better understanding of EV role in tumor promotion/prevention and for the improved HGSC diagnostics.

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	Sample-1.zip	Other
	Sample-2.zip	Other
	Sample-3.zip	Other
	Sample-4.zip	Other
	Sample-5.zip	Other

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A co-culture system of macrophages with breast cancer tumoroids to study cell interactions and therapeutic responses

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