# Phosphoproteomics Reveals L1CAM-Associated Signaling Networks in High-Grade Serous Ovarian Carcinoma: Implications for Radioresistance and Tumorigenesis

## TL;DR

This study shows how L1CAM influences cancer growth and resistance to radiation in ovarian cancer through specific signaling pathways.

## Contribution

The study identifies L1CAM-regulated signaling networks linked to radioresistance and tumorigenesis in ovarian cancer.

## Key findings

- L1CAM knockout reduced cancer stem cell frequency and tumorigenicity in ovarian cancer cells.
- Phosphoproteomics revealed L1CAM-associated pathways contributing to radioresistance via DNA repair and mTORC1 signaling.
- L1CAM-dependent tumorigenesis and radioresistance are linked to phosphorylation of DNA damage response proteins.

## Abstract

Quantitative phosphoproteomics enables the comprehensive analysis of signaling pathways driven by overexpressed cancer receptors, revealing the molecular mechanisms that underpin tumor progression and therapy resistance. The glycoprotein L1 cell adhesion molecule (L1CAM) is overexpressed in high-grade serous ovarian carcinoma (HGSOC) and plays a crucial role in carcinogenesis by regulating cancer stem cell properties. Here, CRISPR–Cas9-mediated knockout of L1CAM in ovarian cancer OVCAR8 and OVCAR4 cells significantly impaired anchor-independent growth in soft agar assays and reduced clonogenic survival following external beam irradiation. In vivo, L1CAM knockout decreased cancer stem cell frequency and significantly decreased tumorigenicity. To uncover L1CAM-regulated signaling networks, we employed quantitative phosphoproteomics and proteomics. Bioinformatics analyses and validation studies revealed L1CAM-associated pathways that contribute to radioresistance through DNA repair processes and mammalian target or rapamycin complex 1 (mTORC1)-mediated signaling. In conclusion, our study established a link between L1CAM-dependent tumorigenesis and radioresistance, both hallmarks of cancer stemness, with phosphorylation of key proteins involved in DNA damage response. This study further emphasizes the value of quantitative phosphoproteomics in cancer research, showcasing its ability to enhance understanding of cancer progression and therapy resistance.