Cancer metabolites organize the tumor microenvironment

Cancer cells are not alone: As cancerous tumors grow unregulated cancer cells engage other cells, in their path of destruction like macrophages which are part of the immune system and endothelial cells which make blood vessels. This collection of non-cancer cells that powers cancer growth is called the tumor microenvironment. How does the tumor microenvironment help cancer cells proliferate even more?

Answering this question is a holy grail of cancer science and holds the key to new therapies. Cancer cells, with their many mutations and unchecked DNA damage, change constantly: they can be a moving target for therapy and develop resistance to drugs that seemed to work at first. The non-cancer cells in the tumor microenvironment are genetically stable. If we knew how these cells interact we could to stop the tumor microenvironment from feeding the cancer, halt cancer growth or even reverse it. On February 28 a team of SKI scientists published a significant advance. The answer—surprisingly—is in metabolism.

All cells rely on metabolism, the engine-like process that requires constant fuel and oxygen to run. Cancer cells have altered metabolisms: they consume lots of oxygen and dump metabolic waste such as lactic acid. Because of this, cancerous tumors should only grow so large before the toxic effects accumulate like pollution in a jam-packed city, and eventually slow cancer growth. This is prevented, however, by tumor-associated macrophages (TAMs) that respond to the harsh environment and start a tissue-repair mechanism to clean it up.

The SKI team started by observing the behaviors of TAMs in a mouse model of cancer. Then, they fabricated tissue-mimetic systems to recreate the same process in vitro. Using this approach they discovered that TAMs respond to low oxygen and to the presence of lactic acid and start producing a vascular endothelial growth factor (VEGF). This growth factor commands endothelial cells to start producing blood vessels—called neo-angiogenesis—a process that can bring new blood to struggling cancer cells, replenishing oxygen and removing toxic waste.

The tissue-repair response of macrophages is normally a good thing: it is how our body heals wounds and clears out toxic waste from muscles after intense exercise. In cancers, however, it can make cells with complementary skills—cancer cells, TAMs and endothelial cells—work together in a terrible way. Rescuing cancer cells from dying because of their own altered metabolism boosts the cancer to grow even more.

The SKI study established a new role for cancer metabolism in the interactions between cancer cells and their microenvironment. These findings lay the foundations for our understanding of cancer development, diagnosis and treatment.

But the study also showed how an interacting team of multidisciplinary scientists could answer a difficult cancer question: Craig Thompson brought his expertise in cancer metabolism, Johanna Joyce her expertise in the tumor microenvironment, and João Xavier his expertise in cancer systems biology, a new field that aims to integrate cancer concepts. Cancers subvert cells with complementary features in their path to destruction; figuring out its complex mechanisms—and new ways to fight them—may require teams of scientist with complementary skills.

The study was spearheaded by Carlos Carmona Fontaine, former postdoctoral researcher at MSKCC who is now assistant professor of Biology at the New York University.

Metabolic origins of spatial organization in the tumor microenvironment
Carlos Carmona-Fontaine, Maxime Deforet, Leila Akkari, Craig B. Thompson, Johanna A. Joyce, Joao B. Xavier. PNAS
[Open Access]

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2016 lab mug

mug2016Carlos Carmona Fontaine, in between finishing his paper and starting his lab at NYU, found time to make the official 2016 Xavier Lab MUG.

Colored in the beautiful parula map, the 2016 mug is the best mug in the world for coffee or tea.

Check out Carlos’s lab website carmofon.org. Join his new lab at NYU Biology and you might make it in time for the first-ever Carmona Fontaine Official Mug.

Read more about the 2016 lab mug and our other mugs in our paraphernalia page.

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NY/B.I.G. meeting

This Friday 10:00am – 6:15pm at NYU
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Kerry Boyle talks about “The metabolomic basis of social behavior” at 10:20-10:35.
More about it: http://biology.as.nyu.edu/object/biology.events.nybig2016

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High school students and teachers at MSK for the 2015 “Major Trends in Modern Cancer Research”

On Tuesday, November 10, MSK hosted the tenth annual “Major Trends in Modern Cancer Research” lecture for high school and college students. The session was moderated by Craig Thompsons and featured Kat Hadjantonakis, Cole Hanes and me. The whole session is on youtube.

High school students at MSK for the 2015

High school students at MSK for the 2015 “Major Trends in Modern Cancer Research”

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Journal covers

During my PhD, 1999-2003, most scientific articles I needed for my research where only available in print. I’d go down to the library and take hours photocopying articles from piles of journals.
I also listened to a lot of CDs and I loved the cover art. I haven’t picked up a CD in a while and I’m pretty sure new CDs are still made, but I don’t know who buys them. The art from new covers goes unnoticed – I haven’t seen one from the last 5 years or more.
Journals still get printed too, but like songs we get the articles online. Grad students don’t spend hours copying in the library, which is great. But some nice covers will go unnoticed.

Covers from the October 15 issue of Cancer Research (collaboration with Richard White's lab) and the December 2015 about issue of Applied and Environmental Microbiology (collaboration with Lars Dietrich's lab and Soren Sorens's lab).

Covers from the October 15 issue of Cancer Research (collaboration with Richard White’s lab) and the December 2015 issue of Applied and Environmental Microbiology (collaboration with Lars Dietrich’s lab and Soren Sorensen’s lab).

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Systems Biology talk at the MSKCC presidential seminars this week

Evolutionary Tradeoffs and the Geometry of Gene Expression Space
Uri Alon, PhD
Senior Scientist, Department of Molecular Cell Biology and Department Physics of Complex Systems
Weizmann Institute of Science
Rehovot, Israel

October 21, 2015 at 4:30 PM
Host: GSK Graduate Students
ZRC Auditorium

This talk is followed by a special seminar “The Emotional Sides of Science: a Guitar Talk”

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Taking statistical pictures of metastasis using zebrafish

Metastasis, the spread of cancer from its primary site to other parts of the body, is when cancer gets really bad. But this process is poorly understood, in large part because it is stochastic. Like the dispersal of plant seeds across a fertile field, metastatic cells could end up in many different places so knowing where metastases will form exactly may seem impossible.
What we need to study physical phenomena that are stochastic is lots of samples and statistics. Studying metastasis across large samples can be very difficult however. Investigating patterns of metastasis in the human body would require compiling dozens of cases while controlling for factors that could influence metastasis in unknown ways like patient age, body-mass-index, exposure to carcinogens, etc. We could use animal models and control for these factors, but common models in cancer research like mice and rats are still quite expensive to run experiments with dozens of samples.

“The zebrafish” (2015) by Silja Heilmann

Enter the glorious zebrafish. The zebrafish is already a powerful model for genetics and development and it is gaining increasing importance in cancer biology. Our lab collaborates with the lab of Richard White in the program for Cancer Biology and Genetics to investigate metastatic spread across dozens of zebrafish. For the past three years Silja Heilmann has been working closely with Rich, Kajan and other members of the While lab to develop protocols and methods for the quantitative analysis of metastasis. The model is a transparent zebrafish called Casper that is great for imaging. In Rich’s lab, they developed a zebrafish melanoma cell line called Zmel1 that expresses GFP. Once injected into adult casper zebrafish, Zmel1 forms primary tumors that later on produce metastasis and we can visualize the process using microscopy.
Silja developed image analysis algorithms that resize and align many pictures of fish together. This procedure allows building a statistical picture of metastatic growth across the whole animal. The detailed picture reveals indeed the strong stochastic nature of metastatic spread, but some patterns start to emerge. Advancements such as these may one day enable a better understanding of metastasis and help in the development of anti-metastasis treatments.

Read the paper:

A quantitative system for studying metastasis using transparent zebrafish
Silja Heilmann, Kajan Ratnakumar, Erin Langdon, Emily Kansler, Isabella Kim, Nathaniel R Campbell, Elizabeth Perry, Amy McMahon, Charles Kaufman, Ellen van Rooijen, William Lee, Christine Iacobuzio-Donahue, Richard Hynes, Leonard Zon, Joao Xavier, and Richard M White. Cancer Research
[PDF]

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