Birkenstok, C. | bioRxiv Science

bioRxiv2026

PTHrP drives aggressive traits in colorectal cancer cells: Implications of tumor-stromal cells

In the tumor microenvironment (TME), dynamic interactions between cells and soluble factors promote tumor progression. We previously demonstrated that parathyroid hormone-related peptide (PTHrP), a TME-associated cytokine, enhances the aggressive phenotype of HCT116 colorectal cancer (CRC) cells, and that conditioned medium from PTHrP-treated HMEC-1 endothelial stromal cells (CM) induces epithelial-to-mesenchymal transition (EMT) in CRC cells. Here, Western blot analysis showed that CM modulates Met receptor expression and activation and promotes cancer stem cell (CSC) traits in HCT116 cells. Since PTHrP induces CPT-11 chemoresistance through Met signaling, we investigated the involvement of the CM-Met axis in this process. Viability assays revealed that CM increases cell number and confers CPT11 resistance through Met activation. Transforming growth factor beta 1 (TGF{beta}1), upregulated in PTHrP-treated HMEC-1 cells, was evaluated as a potential mediator. Its neutralization reversed the CM-induced increase in cell number but did not affect chemoresistance. In silico analyses revealed differences between CRC and normal tissues related to TGF{beta}1 signaling and Met activation, along with positive correlations among the analyzed markers. Immunohistochemical observation of human samples is consistent with our previous findings. Overall, these findings support a role for PTHrP in promoting CRC aggressiveness through coordinated effects on tumor and stromal compartments

cancer biology↗

bioRxiv2026

In Silico study of clinical implication of markers associated with PTHrP regulatory mechanisms and linked to angiogenesis and EMT program of colorectal cancer

Parathyroid hormone-related peptide (PTHrP), encoded by PTHLH, has been implicated in tumor progression through its involvement in epithelial-mesenchymal transition (EMT), angiogenesis, and tumor cell migration. Previous experimental studies suggest that PTHrP may promote these processes in colorectal cancer (CRC), partly through the modulation of factors such as secreted protein acidic and rich in cysteine (SPARC) and vascular endothelial growth factor (VEGFA). These events play a key role in the acquisition of an aggressive phenotype in our experimental models. In this study, we performed an integrative in silico analysis of multiple transcriptomic datasets to investigate the potential role of PTHLH in CRC. Differential expression analysis identified a set of consistently dysregulated genes across independent datasets. Functional enrichment and network analyses revealed that PTHLH expression is associated with biological processes related to extracellular matrix remodeling, EMT, and angiogenesis. Correlation analyses showed a positive association between PTHLH and SPARC expression, while network-based approaches suggested a potential functional connection with VEGFA. To assess the clinical relevance of these findings, survival analysis was performed using publicly available datasets. High expression levels of PTHLH, SPARC, and VEGFA were significantly associated with reduced overall survival in patients. Notably, a combined gene signature based on these three factors demonstrated a stronger prognostic effect than individual genes, indicating enhanced predictive value. These findings suggest that PTHrP is associated with molecular pathways involved in tumor progression and, together with SPARC and VEGF, may contribute to a coordinated regulatory axis with prognostic relevance in CRC, warranting further experimental validation.

cancer biology↗