Modeling the Complexity: Tumor–Microenvironment Interactions in GI Cancers

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Shelly Loewenstein, Surgical Oncology Research Lab, Surgery Division, Tel Aviv Medical Center

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Gastrointestinal (GI) cancers are driven not only by tumor-intrinsic alterations but also by dynamic and reciprocal interactions with the surrounding microenvironment. To investigate these complex interactions, we have developed and applied a suite of complementary model systems that span molecular, cellular, and tissue levels.

We established a method for the detection and classification of circulating tumor cells (CTCs) in peritoneal fluid using Oxford Nanopore MinION sequencing, combined with machine learning algorithms trained on tumor-specific mutational signatures. This approach enables real-time, minimally invasive monitoring of peritoneal dissemination in GI cancers.

In a second model, we performed single-cell RNA sequencing on gastric cancer omental metastatic tissue following treatment with extracellular vesicles (EVs) derived from omental adipocytes of lean or obese patients. Our analysis revealed that EVs from obese adipocytes modulate the transcriptional profiles of multiple cell types within the metastatic microenvironment, suggesting a potential mechanistic link between obesity and tumor progression.

We further employed EVOC (Ex Vivo Organ Culture) technology to functionally profile colorectal cancer (CRC) tumor samples and identify effective, patient-specific combinations of chemotherapeutic agents. By maintaining tumor architecture and microenvironmental context ex vivo, this platform allows for direct assessment of treatment responses and facilitates the discovery of synergistic drug combinations tailored to individual tumors.

Lastly, we developed a 3D spheroid model of pancreatic cancer cells to assess the therapeutic potential of engineered EVs overexpressing the tumor suppressor miR-141. These EVs reduced effectively spheroid size and growth and induced tumor cells apoptosis, highlighting the promise of EV-based miRNA delivery strategies.

Together, these models provide powerful tools for dissecting tumor–microenvironment interactions and advancing precision medicine in GI cancers.