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Normalized Deviation Collaborative
June 29
Association for Women in Science Monthly Coffee Hour
July 12
Physician Efficiency Training: Widescreen Personalization
July 12, 14 and 20
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In This Issue:
- Vrahas Appointed Founding Chair of Orthopaedics
- Romanoff Maintained Relentless Focus on Patient Safety
- Letter from Chief of Staff: Updating Online Profiles
- Two Minutes With …
- Father of Three Thanks Circle of Friends
- FDA Cautions Against Zecuity Patches, High Doses of Loperamide, and Aspirin Overuse
- Case Against Social Media Triumphs in Debate
- Goals of the Anesthesia Pre-Procedure Evaluation Center
- Metabolic Plasticity in Breast Cancer
- Gewertz Lectures About Innovation and Leadership
- Reminder About Block Utilization, Operating Room Access
- The Campaign for Cedars-Sinai Begins Public Phase
- CS-Link Tip: Creating and Editing Lists
- Circle of Friends Honorees for May
Metabolic Plasticity in Breast Cancer
By V. Krishnan Ramanujan, PhD
V. Krishnan Ramanujan, PhD |
Neoplastic transformation is a stochastic step in the life of a breast epithelial cell. Not all the transformed cells survive to become malignant cancers. The holy grail of breast cancer research is to understand how a transformed cell survives within a normal mammary epithelium amid the prevailing regulatory checkpoints and protective mechanisms in a normal tissue environment.
Regardless of their origin, all transformed cells display a variety of adaptive strategies (such as aerobic glycolysis and hypoxia) to increase their survival and proliferative potential. Intriguingly, both these adaptive mechanisms have aberrant mitochondrial metabolism as a common denominator. While aerobic glycolysis is an attempt to increase cancer cell biomass via compromised mitochondrial metabolism in the presence of oxygen, hypoxia is another extreme of mitochondrial shutdown owing to limited oxygen supply within a growing tumor.
While trying to identify the putative mitochondrial defects in human breast cancer cells, our laboratory (Metabolic Photonics Laboratory) uncovered a significant diversity in mitochondrial number, enzymatic activity and response to mitochondrial perturbations between these cells.
Three-dimensional reconstruction of a live mouse tumor spheroid showing the spatial heterogeneity in mitochondrial metabolism. Labeled with mitochondrial metabolic marker (red) and a plasma membrane marker (green). |
Our long-term goal is to identify and understand the metabolic routes by which we could target the metabolic vulnerabilities in cancer cells, thereby making them revert to a nontumorigenic, normal-like phenotype (metabolic plasticity). Toward achieving this goal, we have been making significant inroads by focusing on mitochondrial Complex I, which is the largest enzyme in the electron transport chain and is the least studied enzyme in the context of cancer metabolism.
In an in vitro model system, we recently demonstrated that mitochondrial Complex I deficiency directly led to aerobic glycolysis phenotype that is known to favor tumorigenic growth in a number of breast cancers. In a follow-up in vivo study using human breast cancer xenograft model, we discovered that pharmacological enhancement of mitochondrial Complex I function in aggressive human triple-negative breast cancer cells led to a significant reduction (~70 percent) in tumor growth with a concomitant reduction in aerobic glycolysis phenotype.
These studies gave us a vital clue that mitochondrial Complex I normalization could be a powerful strategy to control breast cancers. By a multidisciplinary approach involving high-resolution metabolic imaging, novel transgenic mouse models and human biospecimens, we are currently focusing on elucidating how we could extend the scope of metabolic plasticity idea to various breast cancer subtypes and to primary and metastatic tumor control.
Principal investigator : V. Krishnan Ramanujan, PhD
Lab : Metabolic Photonics Laboratory, Cedars-Sinai departments of Surgery and Biomedical Sciences
Intramural funding comes from the Department of Surgery, extramural funding from the National Cancer Institute, Susan G. Komen organization and American Cancer Society.