(808.7) Hypoxia Re-Oxygenation Modelling Using Cancer Cells Expressing Cell Cycle and Cell Death Probes to Understand the Dynamics of Resistance Mechanisms

Poster Board Number: A303

Shivanshu Kumar Tiwari (Rajiv Gandhi Centre For Biotechnology Thiruvananthapuram, Kerala, India), T. R. Santhosh Kumar (Rajiv Gandhi Centre For Biotechnology Thiruvananthapuram, Kerala, India)

Background:

Most solid tumors are difficult to treat with conventional cancer drugs.  Non-responsiveness to drugs and the recurrences even after successful treatment are serious problems. Although, extensive studies have been performed to understand the mechanisms of resistance and tumor recurrences, the complex and variable nature of microenvironmental factors that contribute this remains as a challenging topic. 

 Hypoxia is also one of the key factors that play a crucial role in tumor progression. Hypoxia-Induced Factor 1 α (HIF 1-α) are involved in the resistance of hypoxic tumors to radiation therapy as well as conventional drugs. However, the growing tumor is often exposed to hypoxia and re-oxygenation because of the tumor driven hypoxia and occasional angiogenic response that primarily affect the cell cycle and cell death.

Hypothesis:

We hypothesize that the defined models of cell cycle and cell death in the setting of hypoxia-reoxygenation will help us to understand the hypoxia-mediated cell signaling and resistance mechanisms.

Methodology:

We have employed cancer cells expressing cell cycle probe FUCCI to study the dynamics of cell cycle progression during hypoxia and reoxygenation using real-time imaging. Similarly, cancer cells were expressed with real-time probes for cell death, FRET-based caspase sensor to track their long-time fate. These innovative strategies allowed us to visualize both cell cycle and cell death events in hypoxic and re-oxygenation condition and to track the long-time fate of cancer cells.

Results amp;

Conclusion:

We have shown that the hypoxic exposures alter the cells’ ability to undergo apoptosis dynamically after its recovery under normoxia. Initially, the cells adapt to hypoxia through mitophagy dependent manner that alters its cell cycle progression both in normoxia and hypoxia. Despite adaptive mitophagy, hypoxic cells remain sensitive to re-oxygenation and also to cancer drugs owing to the oxidation damage to organelles.

However, rare cells survive during these two events progresses towards expansion with a highly variable mitochondrial density that governs differing functional traits of cell cycle, cell death response, ability to invade and migrate. This functional heterogeneity appears to play a key role in temporally regulated tumor resistance and recurrences.

DST India and
DBT TWAS India