Melanoma mutation likes fat for fuel, study finds

cancer
(Derek I. Batting) #1

Melanoma mutation likes fat for fuel

Diet can modulate growth-spurring effect in mice
EMORY HEALTH SCIENCES

Cancer cells love glucose, the simple sugar the body uses for energy, so a high-fat, low-carb diet should starve them, right?

Not so fast. Research in mice suggests that melanomas and other cancers driven by a particular mutation (BRAF V600E) will grow faster in response to a high-fat diet. In addition, lipid-lowering agents such as statins curb these cancers’ growth, even in the context of a more normal diet.

The results are scheduled for publication in Cell Metabolism.

While the findings cover only one mutation and need to be tested clinically, they sketch out the concept of a “precision diet,” tailored to an individual patient’s cancer.
…
Most cancer cells display enhanced glucose uptake, a phenomenon known as the Warburg effect. A low-carb diet has been tried as a clinical countermeasure in a limited way, mainly in brain cancer. In contrast, a possible implication of the Winship researchers’ results is that people fighting a cancer with a BRAF V600E mutation should avoid low-carb diets.
…
One of the alternative energy sources produced by ketogenesis is acetoacetate. Within cancer cells with the V600E mutation, acetoacetate production is stimulated, the Winship researchers had found. On top of that, acetoacetate binds the mutated B-raf protein and promotes its oncogenic activity, forming a cycle of positive feedback.

The Winship researchers wanted to test whether V600E cancer cells would respond to external acetoacetate. A ketogenic diet with very low carbohydrates, like an Atkins diet, can cause acetoacetate levels in the body to rise. Fasting can also trigger the same effect.

When researchers fed mice a diet with more than 90 percent of its calories from fat, grafted tumors derived from V600E melanoma cells grew faster (twice as large over four weeks) than in mice fed a normal diet. This was not true of tumors derived from melanoma cells with other oncogenic mutations.

Above contains article highlights. Click below to read complete article.

Source: EurekAlert!

Mouse model cautions keto when your melanoma tumor is a BRAF V600E-expressing melanoma
(Derek I. Batting) #2

Highlights
•Dietary fat promotes ketogenesis to enhance BRAF V600E tumor growth
•Hypolipidemic agents inhibit BRAF V600E tumor growth
•Dehydroacetic acid competes with acetoacetate for BRAF V600E binding
•“Precision diet” can lower cancer risk and provide cancer prevention

Summary
Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized “precision diets” that may prevent or delay tumor progression based on an individual’s specific oncogenic mutation profile.

Article published in Cell Metabolism: http://www.sciencedirect.com/science/article/pii/S155041311630643X

(Jamie Hayes) #3

I wonder what kind of fat was used?

(Derek I. Batting) #4

It should be easy enough to find out. Authors Jun Fan, Qun-Ying Lei, and Jing Chen all have contact information available.
Jun Fan: jfan3@emory.edu
Quan-Ying Lei: qlei@fudan.edu.cn
Jing Chen: jchen@emory.edu

#5

Melanomas are also very sensitive to leucine and the mTor pathway. In fact just the amount of leucine released from cellular material during autophagy is enough to sustain melanoma. I wonder if they took this into consideration during the study?

“Although cells in a test tube can be deprived of leucine completely, removing leucine from a mouse or a human is almost impossible, due to large leucine reservoirs in muscles.”

(Alix Hayden) #6

This is very interesting, and it wouldn’t surprise me to learn that certain specific mutations in certain tumours respond differently to different fuels and inputs. I think it’s encouraging to learn more about how to target therapies, and by studying exceptions, we always learn also about the nature of the whole system. I’ll be interested to see the full article when it’s published, thanks for sharing.

(Tim Sheehan) #7

I think the moral of the story here is to follow the regime that best suits your medical condition, there’s no one-size-fits-all approach to dieting that will prevent or assist with every medical condition.

#8

That is certainly true for various amino acids. I find it interesting that fats may also play a role. [Specifically the ketone acetoacetate.]

“Cells can differ in which amino acids they require for survival, and oncogenic transformation may make them liable to the deficiency of a particular amino acid. For example, human fibroblasts with activated c-MYC depend on glutamine (Yuneva et al., 2007), lymphoblastic leukemia cells require tryptophan, methionine, and valine (Gong et al., 2000; Kreis et al., 1980; Ohtawa et al., 1998; Woolley et al., 1974), and several types of solid tumor cells require arginine (Scott et al., 2000). In most cases however, the cellular underpinnings behind the particular amino acid requirements of a cancer cell type are largely unknown, making it difficult to exploit such information to implement anticancer therapeutics.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115736/

(Larry Lustig) #9

I have nothing to contribute directly to this topic but I just want to say that I’m so, so happy to see it discussed in an objective and open manner. In the FB group a similar study was cited a few months and resulted in a piling-on of “they are enemies of fat!” posts.

(Dave) #10

Hmmm I suppose I better not get sunburnt

(Alix Hayden) #11

I saw the same thing in other groups, I think at the time it was motivated by a mouse study where the “subjects” were fed a crazy mix of inflammatory fats, and the conclusion was drawn in headlines that “fat fuels cancer”. This resulted in an immediate uproar of fear driven rants. Not helpful.

(John Walker) #12


TL;DR mouse model cautions keto when your melanoma tumor is a BRAF V600E-expressing melanoma. Always talk to your oncologist about this kind of dietary control and keep up on the science!

Note that this study focused on a cancer, specifically BRAF V600E-expressing melanoma mutant-dependent MEK1 activation in human cancers for those of us spilling ketones. The ketone in question here is acetoacetate.

Caution here:
This is a murine (mouse) model study and the science is behind a paywall. The study calls for a fine-tuned diet in order to keep these kinds of tumors from growing quickly.

So, for those of us Ketonians who are cancer survivors (Stage III-C Colon here, unknown whether I had the mutation mentioned above), there is a new study which cautions against Keto when a specific mutation is present in your tumor.

[Merged topics -carolt]

(Derek I. Batting) #13

Posted here a couple days ago:

[Merged]

(Stephanie Hanson) #14

Does anyone know who funded the study? Just curious.

(Derek I. Batting) #15

Not sure, but there seems to have been a mess of people involved in it.

1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, Georgia 30322, USA
2 Department of Radiation Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, Georgia 30322, USA
3 Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
4 Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
5 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA
6 Department of Dermatology, Emory University, Atlanta, Georgia 30322, USA
7 Atlanta Veterans Administration Medical Center, Atlanta, Georgia 30322, USA

#16

It was a bad idea to begin with…maybe a second reason for ketonians…

(Bacon for the Win) #17

mucosal melanoma is a thing. Has nothing to do with sun exposure. My father never left the house with out sun protection yet melanoma took his life. Cruel irony if you ask me.