# Modulation of Patient-Derived Tumor Organoids by SARS-CoV-2 Variants Across Cancer Types: A Study Combining Morphology, Inflammation, and Whole-Exome Profiling

## TL;DR

This study explores how different SARS-CoV-2 variants affect cancer organoids, revealing variant- and tumor-specific changes in morphology and immune responses.

## Contribution

The study introduces a novel model using patient-derived organoids to investigate SARS-CoV-2 variant-specific interactions with various cancer types.

## Key findings

- The Delta variant caused higher viral loads in lung and breast organoids compared to the Gamma variant.
- Infection led to morphological changes like reduced area and increased circularity across all tumor types.
- Host gene variants in trafficking and immune signaling were linked to differential infection profiles.

## Abstract

Cancer patients are highly vulnerable to severe COVID-19, requiring models that capture tumor–virus interactions. We investigated tumor- and variant-specific effects of SARS-CoV-2 Gamma and Delta infections using patient-derived organoids (PDOs) from metastatic breast, lung, and colorectal cancers. Viral infection was quantified by Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) 24 h post-infection, and morphological changes and immune mediators were profiled. Genomic analysis using whole-exome sequencing was performed to identify contributing host-related gene alterations. The Delta variant produced consistently higher viral loads in lung and breast PDOs, while colorectal PDOs showed variable susceptibility. Infection led to reduced area and perimeter and increased circularity across all tumor types. Immune profiling revealed distinct responses: Gamma decreased Interferon alpha (IFNα) in lung PDOs and increased E-selectin in colorectal PDOs. Delta broadly reduced inflammatory mediators in lung [10 kDa interferon gamma-induced protein (IP-10) and Intercellular adhesion molecule 1 (ICAM-1)] and breast [Interleukin-6 (IL-6), Interleukin-13 (IL-13), and Interleukin-17A (IL-17A)] PDOs, while increasing Macrophage inflammatory protein 1-beta (MIP-1β) in colorectal PDOs. Host gene variants involved in trafficking (FYCO1 and RAB7A) and immune signaling (FOXA2, SFTPD, STAT3, and TET2) were associated with differential infection profiles. These findings show that SARS-CoV-2 induces variant- and tumor-specific morphological and immunological changes in cancer PDOs, highlighting the potential of this model to unravel host–virus interactions and identify genetic factors that shape infection outcomes in cancer.