Thesis Title: Dismantling of the Mesothelial Barrier: A "Two-Hit" Model of Biochemical and Biophysical Stress Driving Ovarian Metastasis in the Peritoneum

Name of the Student: Mr. Satyarthi Mishra

Degree Registered  : Ph.D. Engineering 

Advisor  : Dr. Prosenjit Sen (CeNSE) & Dr. Ramray Bhat (DBG)

Date : 17th October 2025  (Friday), 3:30 PM

Venue:  CeNSE Seminar Hall (Hybrid)

Abstract:

Ovarian cancer happens to be amongst the most lethal of gynaecological malignancies, 
primarily due to its propensity to metastasize through the peritoneum. This thesis 
proposes that successful metastatic colonization by ovarian cancer hinges on a progressive,
 two-part failure of the peritoneal mesothelial barrier, driven by distinct yet possibly 
synergistic biochemical and biomechanical insults. By integrating findings from two distinct 
experimental frameworks, this work presents a unified model of stromal failure that uncovers a 
key vulnerability for therapeutic intervention.

The first chapter demonstrates the biochemical priming of the peritoneum for invasion. 
We demonstrate that elevated levels of the dicarbonyl methylglyoxal (MG)—a hallmark of systemic 
metabolic stress associated with aging and diabetes—critically impair the mesothelium's defensive 
capacity by reducing cell viability, adhesion, and motility. In contrast, ovarian cancer cells thrive 
by upregulating the detoxifying enzyme Glyoxalase-1 (GLO-1), effectively weaponizing the toxic 
microenvironment to establish a path for invasion.  

The second chapter investigates the catastrophic mechanical breach of this pre-weakened barrier. 
Using a first-of-its-kind distensible peritoneum-on-chip platform that recapitulates the physical
 forces of malignant ascites, we found that mechanical distension alone significantly compromises
 mesothelial integrity, leading to decreased viability and disordered cell motility. Consequently,
 this mechanically weakened barrier is profoundly more susceptible to colonization, with a significantly 
higher degree of attachment followed by spreading of metastatic ovarian spheroids when compared to 
non-distended control conditions.  

Together, this research establishes a "two-hit" model where biochemical glycation via dicarbonyl 
stress acts as a "first hit" that sensitizes the peritoneum, while the "second hit" of mechanical 
distension due to ascites causes a catastrophic failure of this barrier. To conclude, the thesis 
identifies ovarian cancer's dependence on GLO-1 as a critical metabolic vulnerability, suggesting 
that inhibition of this enzyme might act as a potential therapeutic strategy to prevent metastatic 
progression by dismantling the cancer's ability to engineer its own invasive niche.