Research led by Oncode Investigator Maria Rodríguez Colman at the University Medical Center Utrecht (UMC Utrecht) demonstrates a new role for lactate, which is constantly produced in the body during normal metabolism and exercise, as a master regulator of cancer stem cell identity, as is described in the scientific journal Cell Metabolism. These findings are the result of a multidisciplinary collaboration in which multiple Oncode Investigators joined forces to unravel complex cancer biology, with Boudewijn Burgering (UMC Utrecht), Jarno Drost (Princess Máxima Center), the Organoid Group (Hubrecht Institute) and Michiel Vermeulen (Radboud University).
Decoding Cancer Metabolism: Lactate Shapes Tumor Development
For more than a century, scientists have known that cancer cells process nutrients and generate energy differently from healthy cells. This metabolic shift, first described by Otto Warburg in the early 20th century, leads cancer cells to consume large amounts of glucose and convert it into lactate. While lactate was originally considered a mere waste product, it is now recognized as a factor that helps cancer cells evade the immune system and stimulate blood vessel formation.
However, why cancer cells adopt this metabolic change and whether it influences tumor progression remain open questions. Healthy tissues consist of diverse cell types that work in coordination to perform complex tasks, but tumors disrupt this balance. Genetic mutations drive uncontrolled growth, yet tumors still exhibit cellular diversity, including cancer stem cells—cells with the ability to self-renew and fuel tumor expansion.
Why this diversity persists and how metabolism influences it remain poorly understood. In this recent study from the Rodriguez Colman Lab, Nguyen and colleagues provide new insights into this puzzle. Using colorectal cancer organoids – which are miniature, 3D tumor models derived from patients – in combination with advanced microscopy, they tracked metabolite changes and cell diversity at the single-cell level. This allowed them to observe how tumor cells divide and evolve over time.
A New Role for Lactate: Master Regulator of Cancer Stemness
Their findings reveal a previously unrecognized role of lactate in shaping tumor development. While traditionally viewed as a metabolic byproduct, lactate is, in fact, a key regulator of cancer cell identity. The researchers discovered that lactate, produced abundantly by differentiated cancer cells, accumulates in the tumor microenvironment and actively maintains cancer stemness. It does so by disrupting normal cell fate commitment, effectively preventing tumor cells from fully differentiating.
Strikingly, they found that lactate’s influence extends beyond metabolism—it epigenetically rewires the tumor’s genetic landscape. By modifying chromatin organization, lactate activates the oncogene MYC, a master regulator of cell growth and proliferation, driving cancer cells to revert to a stem-like state. This metabolic feedback loop may help explain why tumors maintain a population of cancer stem cells, a key factor in therapy resistance and disease progression.
Understanding how metabolism shapes tumor behavior could open new therapeutic opportunities. While targeting metabolism alone has proven difficult, this study suggests an alternative approach: manipulating tumor dynamics. Specifically, adjusting the proportion of dividing cancer cells or altering cell cycle timing may impact the effectiveness of conventional chemotherapies that target DNA replication and repair.
The findings of this research are published in Cell Metabolism.