Cancer is a complex multi-factorial disease with one of the most challenging aspects being cancer cells’ exceptional ability to survive and thrive through stress. Assistant Professor Dr. Deepali Bhandari of the Biochemistry department hopes to find a way to destroy these cells, but first she needs to understand what makes them survive.
Bhandari studies endoplasmic reticulum (ER) stress in cancer cells. The ER is a network of membranes located throughout the cell. It serves as the manufacturing and packaging system for the cell and any perturbations in its functions such as misfolding of proteins generate ER stress.
“While the ER-stressed cells initially respond by trying to fix the problem, they activate a death program if the stress becomes chronic and is not resolved in a timely fashion,” she said.
Bhandari likened the situation to a person who seeks therapy to deal with his or her stress. She said if the stress becomes chronic and therapy isn’t working, that person could slip into clinical depression and even take extreme steps. The same can happen on a cellular level.
“Cells start killing themselves off because they don’t see a way out,” Bhandari said. “They are overworked, overwhelmed, and eventually succumb to the stress.”
Diabetes, Parkinson’s disease, and myocardial infarction are among the diseases that can occur when cells become stressed and die off. Cancer is another extreme, she said. Cancer cells thrive under duress.
Bhandari is working to identify the proteins and signaling mechanisms that play a role in how cells make this life-or-death decision in the face of ER stress. She hopes to discover, in particular, key proteins, or pathways, that help cancer cells survive through ER stress.
“Cancer cells experience ER stress because they are dividing so fast, making a lot of proteins and are growing in a less than ideal environment — there isn’t enough space, not enough oxygen — yet they keep surviving. Somehow they find a way to rewire their signaling programs towards one main goal – Survival!”
Funded by a National Institutes of Health grant called Support of Competitive Research, Bhandari and her research group are studying why this happens. What is so different about pancreatic beta cells (cells that make and secrete insulin) and cancer cells? Why does one cell choose death when stressed and the other prosper?
Clariss Limso, a student on Bhandari’s team, called the relatively new research into linking ER stress to disease an exciting field.
Bhandari said that when cells experience ER stress, they use an adaptive mechanism known as the unfolded protein response (UPR) to restore ER proteostasis, which is the process that regulates proteins and maintains the health of the cell.
UPR can trigger both cell survival or self-destruction signals. According to cell.com, the UPR is involved in the acquisition of many malignant characteristics that allow tumor growth. It also reported that ER stress is a common feature of different types of blood and solid cancers.
To study how this works, Bhandari and her research team grow cancer cells in petri dishes and stress them by using chemical inducers.
“Then we examine various signaling pathways to see which ones are being activated. Our goal is to determine if we can make cancer cells kill themselves by inactivating/depleting a crucial protein from that pathway” she said.
Bhandari said being able to survive through ER stress can also endow cancer cells with chemo-resistance.
“Cancer cells display an amazing ability to adapt and survive through adverse conditions and environment which makes finding a cure for cancer very difficult,” she said. “By studying the pathways that endow cancer cells with this ability at a fundamental level, we hope to ultimately contribute towards finding better ways to treat cancer.”