# Suppression of Ovarian Cancer Cell Proliferation Is Associated with Upregulation of Cell-Matrix Adhesion Programs and Integrin-β4-Induced Cell Protection from Cisplatin

## TL;DR

This study shows that high levels of integrin beta 4 in ovarian cancer cells slow growth but increase resistance to chemotherapy.

## Contribution

The novel finding is that integrin beta 4 influences both cancer cell growth and resistance to Cisplatin.

## Key findings

- High integrin beta 4 levels correlate with lower cell growth genes in ovarian cancer patients.
- Blocking cell growth with Palbociclib increases integrin beta 4 and reduces Cisplatin effectiveness.
- Overexpression of integrin beta 4 slows cancer cell growth but makes them more resistant to chemotherapy.

## Abstract

Ovarian Cancer (OC) cells can become resistant to chemotherapy, but it is unclear how their ability to attach to the surrounding environment affects this process. First, we analyzed patient databases and found that when integrin beta 4, a protein important for cell attachment, was high, the genes driving cell growth were lower, and vice versa. Next, we blocked cell growth with a drug called Palbociclib and unexpectedly saw that integrin beta 4 increased, reducing the cells’ response to Cisplatin (a common chemotherapy). We confirmed these findings in OC cell lines and in patient-derived samples. Moreover, over-expressing integrin beta 4 caused cells to grow more slowly yet become more resistant to Cisplatin. These findings highlight how integrin beta 4 and the surrounding cell environment shape both cancer growth and treatment response, suggesting new ways to improve OC therapies.

Background: The role of extracellular matrix adhesion components in modulation of the treatment sensitivity of ovarian cancer (OC) cells is not well understood. Methods and Results: Analysis of ovarian cancer TCGA gene expression datasets revealed an inverse correlation between genes involved in cell-cycle progression and extracellular matrix interactions, including laminin-binding receptor integrin β4, a major component of extracellular matrix adhesion. Gene ontology analysis also showed that in patient populations with low ITGB4 expression, cell cycle-related programs were activated, while in populations with high expression of ITGB4, the activation of these cell cycle programs was lower. Suppression of proliferation with the CDK4/6 inhibitor Palbociclib stimulated integrin β4 expression and induced protection against Cisplatin in cells naturally expressing low levels of integrin β4. Additionally, ovarian cancer patient-derived organoids showed reduced Cisplatin sensitivity when pretreated with Palbociclib. Our data also showed that integrin β4 overexpression decreased ovarian cancer cell proliferation and at the same time, attenuated Cisplatin response. Conclusions: In summary, our investigations support the idea that integrin β4, and likely its matrix ligands, play critical roles in the regulation of cellular growth and the chemoresistance of ovarian cancer cells.