Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer
A significant clinical challenge in patients with colorectal cancer (CRC), which adversely impacts patient survival, is the development of therapy resistance leading to a relapse. Therapy resistance and relapse in CRC is associated with the formation of lipid droplets (LD) by stimulating de novo lipogenesis (DNL). However, the molecular mechanisms underlying the increase in DNL and the susceptibility to DNL-targeted therapies remain unclear. Our study demonstrates that colorectal drug-tolerant persister cells (DTPs) over-express Lipin1 (LPIN1), which facilitates the sequestration of free fatty acids into LDs. The increased expression is mediated by the ETS1-PTPN1-c-Src-CEBPβ pathway. Blocking the conversion of free fatty acids into LDs by treatment with statins or inhibiting lipin1 expression disrupts lipid homeostasis, leading to lipotoxicity and ferroptotic cell death in both DTPs and patient-derived organoids (PDOs) in vitro. Ferroptosis inhibitors or N-acetylcysteine (NAC) can alleviate lipid ROS and cell death resulting from lipin1 inhibition. This strategy also significantly reduces tumor growth in CRC DTP mouse xenograft and patient-derived xenograft (PDX) models. Our findings highlight a new metabolic vulnerability in CRC DTPs, PDO, and PDX models and provide a framework for the rational repurposing of statins. Targeting the phosphatidic acid (PA) to diacylglycerol (DAG) conversion to prevent lipid droplet formation could be an effective therapeutic approach for therapy-resistant CRC.
Authors
- Nandini Verma (ORCID: https://orcid.org/0000-0001-5260-8999)
- Nazia Chaudhary (ORCID: https://orcid.org/0009-0008-8993-5975)
- Poonam Gera (ORCID: https://orcid.org/0000-0001-7709-1594)
- Dharamvir Jain (ORCID: https://orcid.org/0000-0003-3482-8001)
- Ashwin Jainarayanan (ORCID: https://orcid.org/0000-0003-3523-1477)
- Prachi Patil (ORCID: https://orcid.org/0000-0002-5809-6282)
- Sorab N. Dalal (ORCID: https://orcid.org/0000-0001-6883-7550)
- Avanish Saklani (ORCID: https://orcid.org/0000-0003-4498-7612)
- Siddhesh S. Kamat (ORCID: https://orcid.org/0000-0001-6132-7574)
- Alessandro La Ferlita (ORCID: https://orcid.org/0000-0002-3680-3177)
- Rahul Thorat (ORCID: https://orcid.org/0000-0001-5059-0342)
- Arnab Chakraborty (ORCID: https://orcid.org/0000-0001-5812-3984)
- B Akshaya
- Lalit Sehgal
- Anusha Shivashankar (ORCID: https://orcid.org/0000-0002-3692-3996)
- Mufaddal Khuzema Kazi (ORCID: https://orcid.org/0000-0002-3295-0006)
- Bhagya Shree Choudhary (ORCID: https://orcid.org/0009-0006-1738-9683)
- Nileema Khapare
- Showket Yahya (ORCID: https://orcid.org/0000-0001-6509-7032)
- Eeshrita Jog (ORCID: https://orcid.org/0009-0002-2618-9166)
- Aakash Chandramouli (ORCID: https://orcid.org/0009-0004-8553-1202)
- Bushra K. Khan
- Afiya Dalwai
Institutions
- Indian Institute of Science Education and Research Pune (IN)
- Homi Bhabha National Institute (IN)
- University of Exeter (GB)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- Tata Memorial Hospital (IN)
- University of Oxford (GB)
- Advanced Centre for Treatment, Research and Education in Cancer (IN)
Publication Details
- Journal
- Redox Biology
- Published
- 2024-12-11
- DOI
- https://doi.org/10.1016/j.redox.2024.103458
- Citations
- 15
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 4.28