Author interview: Eeshrita Jog, with a master in Biotechnology, joined as a Research Assistant under Dr. Nazia Chaudhary at ACTREC in 2022 when she conducted this study. She is now a pre-doctoral fellow at the University of Pittsburgh.
Lab: Dr. Nazia Chaudhary, The Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) -Tata Memorial Centre. Twitter
Research Summary: Our study identifies Lipin-1 as a key regulator of lipid droplet formation in drug-tolerant colorectal persister cells and shows that inhibiting Lipin-1 can induced ferroptotic cell death.
What was the core problem you aimed to solve with this research? A big problem in treating colorectal cancer (CRC) is therapy resistance, which can lead to relapse and poor patient survival. Therapy-resistant CRC cells increase lipid droplet formation by increasing de novo lipogenesis; however, the mechanisms behind this process and how we can target it for therapeutics are still unclear. Our study aimed to identify the key regulators in CRC DTPs and determine whether blocking lipid droplet formation could be an effective therapeutic strategy.
How did you go about solving this problem? We found that Lipin-1 gene was significantly upregulated in drug non-responder patient cohorts compared to responders. To validate this, we developed drug-tolerant persister cells, an in-vitro model system that mimics clinical scenarios to study CRC cells that persist despite high doses of chemotherapeutic treatment. We looked at lipid metabolism in CRC DTPs and found that they overexpress Lipin-1, which is important for storing free fatty acids in lipid droplets. Through molecular studies, we identified that the ETS1-PTPN1-c-Src-CEBPβ signaling pathway upregulates Lipin-1. We also tested whether blocking Lipin-1 activity using statins and inhibitors can trigger ferroptotic cell death (iron-mediated cell death).
This study reveals the novel molecular mechanisms driving lipid droplet formation and therapy resistance in colorectal cancer, offering a novel therapeutic strategy targeting lipid metabolism to overcome drug tolerance. — Dr. Nazia Chaudhary
How would you explain your research outcomes (Key findings) to the non-scientific community? Cancer cells grow really fast, and that’s why they have developed different ways to fuel and protect themselves. One such method is storing fats in tiny droplets that act as shields against treatments like chemotherapy. Our research found that if we block a protein called Lipin-1, it stops the cancer cells from storing fat, which renders them vulnerable to a unique type of cell death called ferroptosis- which is caused by the build-up of damaged fats in cells. Additionally, we found that treating cancer cells with statin, a common cholesterol-lowering drug, can block fat storage and make cancer cells sensitive to chemotherapy. This is important as statins can be repurposed to fight colorectal cancer chemotherapy resistance!
What are the potential implications of your findings for the field and society? This study shows us that targeting Lipin-1 or lipid metabolism could be a new way to target therapy-resistant CRC. Existing, FDA-approved drugs like statins could be repurposed to block lipid storage in CRC cells. Incorporating statins into existing treatments could be a faster, bench-to-bedside, and cost-effective approach to reduce patient relapse rates. This can also be extended to other cancers that rely on lipid metabolism for survival.
What was the exciting moment during your research? One such moment during my research was discovering that statins, typically used for cholesterol-related diseases, can reduce the number of lipid droplets in cancer cells. This was exciting as the realization that a common drug could have an unexpected impact on a disease as complicated as cancer was interesting. It also reinforces the idea that we already have many natural or modified tools to help us fight various diseases; we just need to discover how to repurpose these drugs. Also, how collaborative research combining different approaches with bioinformaticians (Dr. Ashwin, Dr. Lalit), chemical Biologists (Dr. Siddhesh Kamat), clinicians (Dr. Avanish Saklani, Dr. Mufaddal Kazi) and basic scientists (Dr. Sorab N. Dalal) can help in discovering the new unexplored mechanism of therapy resistance
Reference: Jog E et al. Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer. Redox Biol. 2025 Feb; 79:103458. doi: 10.1016/j.redox.2024.103458.
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