Microbiome Landscapes in Squamous Cell Carcinoma Tissue Microenvironments: A Comparative Analysis

Squamous cell carcinoma (SCC) is one of the most prevalent human cancers. While anatomically distinct, SCCs exhibit diverse similarities in etiology and molecular. The extent to which different SCCs share microbial landscapes within the tumor tissue microenvironment remains unclear.

We analyzed RNA sequencing data from 419 SCC samples across five anatomical sites: cutaneous (CuSCC), esophageal (ESCC), lung (LSCC), head and neck (HNSCC), and cervical (CeSCC). Differential microbial abundance between tumor and adjacent normal tissue was assessed using multivariable linear models implemented in MaAsLin2. For each anatomical site, an independent external validation cohort was included (totaling 156 samples) to validate key microbial findings using the area under the receiver operating characteristic curve (AUROC).

The five SCC cohorts shared 28 shared core bacterial genera, with Staphylococcus was widespread and had the highest relative abundance (mean 13.74%) in all cohorts. ESCC, HNSCC, and LSCC exhibited more similar dysregulated microbiota, with Clostridioides showing the most significant up-regulation in tumor relative to adjacent tissue (the mean model coefficient value, coef = 3.26). Notably, Bradyrhizobium (CeSCC, CuSCC, LSCC, mean coef = -2.58), Massilia (in CeSCC, ESCC, HNSCC, mean coef = -1.99), Providencia (in CeSCC, HNSCC, LSCC, mean coef = 0.93), and Ralstonia (in CuSCC, ESCC, HNSCC, mean coef = -0.52) displayed significant differential expression across multiple cohorts, as confirmed in the validation cohorts (AUROC > 0.6).

Despite the absence of a common dysbiotic microbiota among SCCs due to anatomical differences, potential similarities in adjacent sites suggest a unified disease perspective and may pave the way for novel preventive and therapeutic strategies.