Metabolic Signaling and the Epigenome

Julie-Aurore
Losman
,
MD, PhD
Dana Farber Cancer Institute
Kathryn
Wellen
,
PhD
University of Pennsylvania

Forum Description

Metabolic reprogramming and epigenetic deregulation have both emerged as hallmark features of cancer cells. Although cancer epigenetics and cancer metabolism have been largely viewed as distinct fields, there is a growing appreciation that the metabolic and epigenetic states of cells are highly intertwined. Metabolic programs determine the abundance of key metabolic intermediates such as methyl and acetyl donors that are substrates for the epigenetic enzymes that covalently modify histones and DNA. Conversely, epigenetic programs regulate the expression of metabolic genes, thereby altering the metabolome. As such, epigenetic regulators are highly responsive to metabolic cues and vice versa. In cancer in particular, metabolic signaling to the epigenome plays a critical role in tumorigenesis by coordinating gene expression programs and cellular differentiation, energy supplies, proliferation, and apoptosis. Understanding the links between metabolism and epigenetics has the potential to identify novel molecular targets to treat cancer.

The 2018 Focus Meeting on Metabolic Signaling and the Epigenome will bring together current and emerging leaders whose work bridges the metabolism-epigenetics interface to discuss their work and to explore its potential as a novel area for therapeutic intervention.

Forum Summary

On behalf of the attendees of the Forbeck Focus Meeting on Metabolic Signaling and the Epigenome, we would like to thank the Forbeck Foundation for organizing and sponsoring this exceptional meeting. We all feel that the meeting was extremely useful and that the discussions that took place at the meeting will have an important impact on our work. In fact, several collaborations have already begun based on discussions during the meeting. Below, we have briefly summarized just a few of the issues that were discussed during the meeting.

The interplay of epigenetics and nutritional signals in normal and cancer cells.
One of the central themes of the meeting was the question of how changes in nutrient availability signal to the epigenome and how the epigenome maintains homeostasis in the face of nutrient deprivation. This topic was first introduced by a pair of excellent back-to-back talks by Mei Kong and Jason Locasale. Jason discussed his work on developing metabolomic approaches to study the interplay between central carbon metabolism and acetate production, as well as one-carbon metabolism and histone methylation. He discussed how methionine availability may regulate gene expression by controlling the width of histone methylation peaks. Later in the meeting, Rusty Jones, Jordan Meier, and Katy Wellen discussed similar themes in their talks. Katy discussed the dual role of acetyl-CoA availability in maintaining metabolic homeostasis (by regulating lipid metabolism), and epigenetic homeostasis (by regulating histone acetylation). She went on to discuss evidence that the nucleus may be a distinct metabolic compartment, pointing to a need for local acetyl-CoA production within the nucleus. Jordan Meier is using chemical biology approaches to understand the metabolic regulation of acetyltransferases. He discussed novel findings related to RNA acetylation that might also be linked to metabolism. Rusty Jones is using state-of-the-art approaches to study metabolism of T cells in vivo and presented his work on how nutrient availability and one-carbon metabolism impacts different aspects of normal T cell activation, including T cell expansion and induction of histone methylation, and touched upon how these pathways could be therapeutic targets in autoimmune diseases. John Denu further expanded on this theme later in the meeting when he discussed how cells are able to maintain their chromatin structure during times of metabolic stress when metabolites that are utilized to post-translationally modify histones are depleted. Mei Kong took this theme in a different but complementary direction. She discussed the role of nutritional stress on cancer cells, with a particular focus on how nutrient deprivation can actually promote specific oncogenic pathways by altering chromatin structure, and showed data that suggest that nutrient supplementation, specifically glutamine supplementation, can have anti-tumor effects. Finally, Josh Rabinowitz gave a fascinating talk where he challenged the paradigm that glucose is the primary source of carbon that feeds into the TCA cycle, instead arguing that lactate is the principle circulating carbon carrier. His talk stimulated a robust discussion about why the preferred carbon source for most tissues would be lactate rather than glucose.

How metabolic and epigenetic reprogramming contributes to aging.
Another recurrent theme over the course of the meeting was the question of how metabolic and epigenetic signals contribute to aging. Paolo Sassone-Corsi discussed his work on how the circadian clock coordinately regulates cellular metabolism and chromatin structure to ensure that ‘aging’ occurs in a synchronized manner in all the cells of an organism. Andrew Dillan discussed his work in C. elegans that focuses on the role of the mitochondrial proteotoxic stress on normal aging. He presented very interesting data that suggest that mitochondrial proteotoxic stress induces a mitochondrial unfolded protein response that is regulated, at least in part, by the histone demethylase PHF8. This finding provides a potential mechanism by which nuclear chromatin structure regulates how cells respond to mitochondrial signals, and how mitochondrial signals contribute to aging. John Denu also touched upon this theme in his talk on how chromatin structure is maintained, discussing mechanisms that mitigate age-associated dysregulation of epigenetic homeostasis.

The interplay of epigenetics and hypoxia and other forms of metabolic dysregulation in cancer.
This was another central theme of the meeting and our discussion began early on, with a talk by Christian Frezza. Christian is studying the role of the TET family of 5-methylcytosine hydroxylases in renal cancer. A subset of renal cancers harbor loss-of-function mutations in fumarate hydratase (FH) that result in intracellular accumulation of fumarate. Fumarate is a potent inhibitor of TET activity, and Christian has found that cancers that harbor FH mutations have global increases in DNA methylation and decreases in hydroxymethylation. He also presented interested data on the kinetics of response to FH deletion, finding that certain effects precede fumarate accumulation. Bill Kaelin has made major contributions to our understanding of the role of HIF (hypoxia-inducible transcription factor) in renal cancer, and he gave Christian a number of ideas of how to distinguish the specific contributions of HIF transcriptional activity and fumarate-mediated epigenetic dysregulation in oncogenic transformation of renal cancer. Lucy Godley spoke immediately after Christian, and her talk dove-tailed his perfectly. Lucy is studying DNA hydroxymethylation in pediatric neuroblastoma. She has found that neuroblastoma cells grow better under hypoxia than normoxia and that, under hypoxia, neuroblastoma cells have increased 5-hydroxymethylation. This finding is somewhat surprising given that TET enzymes are oxygen-dependent enzymes and would be expected to be inhibited in low-oxygen states. Lucy has found that TET1 is a HIF target gene, which may explain this seeming contradiction. Lucy is currently working to determine if TET1 and HIF interact directly, which would provide a mechanism by which cellular metabolism (oxygen status) and chromatin structure (DNA methylation) can directly talk to one another. Julie Losman also discussed how metabolic dysregulation can induce cancer-promoting epigenetic changes, specifically in the context of IDH mutant leukemia. She has identified a novel downstream target of mutant IDH, the KDM5 family of histone demethylases, that plays an important role in mutant IDH-mediated leukemogenesis. She is interested in expanding these studies into IDH-mutant solid tumors and had an opportunity to discuss different approaches she might take with Lucy, Bill, Christian and Jordan. Oliver McDonald discussed the role of metabolic and epigenetic rewiring of tumor cells in cancer metastasis. How a localized cancer acquires the ability to metastasize is one of the central questions in oncology. Although it was previously assumed that additional mutations are acquired by localized cancers that permit the cancers to spread, extensive sequencing efforts of paired samples of primary and metastatic tumor tissues has failed to find such a ‘metastasis mutation.’ Oliver has an intriguing hypothesis that tumor cells that escape primary tumors undergo metabolic rewiring to maximize their ability to survive and grow in different environments. This rewiring is not genetic but epigenetic, and therefore is highly adaptable to different environmental conditions. Lydia Finley also discussed the role of metabolism in cancer, but with a somewhat different focus. Whereas the other talks largely explored how dysregulation of metabolic enzymes contributes to cellular transformation, Lydia is studying how loss of p53, a central regulator of the cell cycle and one of the most frequently mutated tumor suppressors in cancer, directly induces metabolic changes and how this metabolic regulation may contribute to tumor suppression, possibly via regulation of TET enzymes. She presented data to suggest that reversal of the metabolic changes induced by p53 loss is sufficient to recapitulate the effects of p53 restoration in cancer cells. The talk by Karen Vouden further expanded upon the theme of ‘non-canonical’ functions of p53 in cancer cell metabolism. Whereas Lydia focused on the tumor suppressive effects of p53, Karen presented data to suggest that p53 can also play a role in promoting cancer by modulating anti-oxidant responses. She cautioned that efforts to restore p53 activity in p53-mutant cancer cells may not have the intend effect if, indeed, p53 can have tumor-protective effects. This idea, that abnormal cellular metabolism can be a liability in cancer cells, was also explored by Bill Kaelin in his talk on IDH mutant glioma. He presented data from a synthetic lethal screen of IDH mutant glioma that suggests that IDH mutant glioma cells are particularly dependent on the transaminases BCAT1 and BCAT2 as a source of glutamate.

How to overcome the technical challenges of studying rare cancers.
This discussion was initiated by Martine Roussel, who was the first speaker at the meeting. Martine studies pediatric medulloblastoma, and her work up to this point has largely focused on characterizing pediatric medulloblastomas molecularly and histologically. She has found that pediatric medulloblastomas harbor very few mutations and those mutations that are present tend to be in epigenetic regulators and in MYC. This suggests that these tumors arise from combined metabolic and epigenetic dysregulation. Martine has undertaken a series of experiments to determine whether the epigenetic mutations she has identified are indeed drivers of pediatric medulloblastoma and she presented very interesting data suggesting that either loss of components of the Polycomb Repressive Complex (PRC2) or loss of the histone lysine demethylase KDM6A can promote tumor growth. This is somewhat surprising given that PRC2 and KDM6A have opposing biochemical functions in cells. Martine is currently working to functionally validate her findings. One of the challenges she is facing is that pediatric medulloblastoma cells are very difficult to culture. Oliver McDonald, Josh Rabinowitz and Lucy Godley made a number of insightful suggestions about culture conditions that might make Martine’s experiments more feasible, including growing the tumor cells in special ‘human serum-like’ media and growing the tumor cells under hypoxia. Another notable discussion point during Martine’s talk was that Lucy has a long-standing interest in profiling the 5-hydroxymethylcytosine landscape in primary pediatric medulloblastoma, but she has not had access to sufficient patient samples to do this analysis. She and Martine spoke at length during the meeting and are planning to start a collaboration to ask if DNA methylation is dysregulated in pediatric medulloblastoma. The larger issue of how to minimize artifacts when epigenetically profiling cancer cells was also touched upon during Julie Losman’s talk. Julie is studying the role of histone demethylases in leukemia and is looking for a way to reliably profile histone modifications in primary IDH mutant AML cells. John Denu presented a method to comprehensively profile histone modifications that was of particular interest to Julie, and she and John had an opportunity to discuss how such a profiling experiment might be accomplished with primary cells, and they discussed what types of samples would work best as controls for that experiment.

A few comments from attendees:
“I cannot express my gratitude for giving me the possibility to attend this unique meeting. As discussed in person, I found the format of the event quite interesting, since I had the opportunity to discuss the broad implications of our recent findings with some of the best scientists in our field, yet maintaining an informal a friendly environment. All the talks gave me some powerful insights and ideas for new projects and, hopefully, some collaborations. In conclusion, I am very impressed by the efforts of the Forbeck family to push the boundaries of research via these meetings so much that I am thinking of organizing with them an event here in the UK.”

“I found the discussion of metabolism really useful for my thinking about my own work and am thinking about how I can incorporate some of what I have learned into our studies.” “Thank you Forbeck Foundation for the opportunity to attend a once in a lifetime Think Tank on epigenetics and metabolism. Amazing discussions that will foster new approaches to cancer treatment and prevention.

Venue & Travel Information

Geneva National Resort

1221 Geneva National Avenue, South

Lake Geneva, WI 53147

262-245-7000

Travel Forms

Travel forms are due 30 days prior to the start of the meeting to allow enough time to plan transportation.

Milwaukee's General Mitchell International Airport (MKE) is the preferred airport as it is only 45 minutes from the meeting location.

  • Arrivals - Thursday around 1 PM, 3 PM and 5 PM
  • Departures - Sunday around 10 AM and 12 PM

Chicago's O'Hare Airport (ORD) is 1 1/2 hours from the meeting location without traffic. The Foundation tries to prioritize International Flights and situations where flying into ORD is significantly cheaper than connecting to MKE. The times below are for guidance only, and depending on the volume of travelers, we may add an additional shuttle to and from the airport.

  • Arrivals - Thursday around 3 PM
  • Departures - Sunday around 10 AM
TRAVEL FORMS DUE:
August 13, 2018
submit travel form

Travel Policy

Please familiarize yourself with our policies and procedures for travel. We truly appreciate you taking the time to participate in this meeting. As you make your plans, please remember that we are a nonprofit organization dependent on donations and volunteers. We do NOT pay for upgrades, change fees, incurred costs resulting from a flight change, transportation to or from your local (home side) airport, meals or other incidentals.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.
  • Spouses are welcome to come with you at their own cost but are not allowed to attend the meeting. Please no children.

What the Foundation Pays

Accommodations and meals are provided by the foundation during the meeting. Airfare will be covered only if booked through our travel agent. The Foundation will also cover airport transportation on the meeting side at the designated shuttle times. You can select not to utilize Foundation arranged transportation at your own expense when completing the travel form. Once your travel form is received your accommodations and airport transfer will be confirmed. Please let us know of any food allergies or other information we should be aware of on the travel forms.

  • If you would like your airfare covered by the Foundation, you must book with our travel agent. Note we do not cover upgrades, changes, late bookings, etc.
  • Flights must be booked at least 30 days prior to the meeting to confirm your accommodations and airport transfer.
  • As a nonprofit we utilize volunteers and other methods to maximize our efforts (or our donor support) when making accommodations and arranging ground transportation. Ground transportation will be provided upon your arrival either by a foundation volunteer or arranged shuttle. You will be provided airport transportation information the week of the meeting. We do not reimburse for home side airport transfer or incidentals while traveling.

Abstracts

Abstracts are due 30 days prior to the start of the meeting to allow enough time to prepare the meeting book.

The abstracts should be only one or two paragraphs outlining the theme of your presentation and should reflect the objective and spirit of the meeting (see above). Abstracts will be circulated about one week before the meeting. The meeting organizer will start requesting them a month before the meeting.

abstracts DUE:
August 13, 2018
submit abstract

Meeting Structure

The meeting structure has been developed over years of experience.

  • Participants have approximately 45 minutes, depending on the number of participants, for their presentation and discussion. The presentation is meant as a conversation start and should last about twenty minutes briefly covering background information and areas that are new or need further input. This should be structured in such a way as to lead to a lively discussion. Participants are encouraged to interrupt to ask questions or start discussions.
  • A MAXIMUM of 5 slide equivalents per presentation is allowed (Power point slides should not contain more than one graph or gel per slide and no more than 5 bullet points to stress the points being made by the presenter.) We appreciate cooperation with the spirit of this guideline. Handouts are welcome but should be distributed before sessions.
  • Everyone is expected to actively participate in every session and discussions.
  • The time spent at the meeting is relatively short, so please be familiar with papers received prior to the meeting.
  • It is very important that you commit to all sessions of the 2 days of meetings.

Forbeck Scholars Participation

Scholars are selected for each Forbeck Forum. These are outstanding junior clinical or post-doctoral fellows selected based on the quality and relevance of science.

  • Scholars present for 30-45 minutes, depending on the number of participants
  • The same presentation rules apply for scholars
  • After the Forum you are selected to attend, you will attend three years of Scholar Retreats held in Lake Geneva, WI. If you attend a Fall Forum, you will attend the Spring Retreat. If you attend a Spring Forum you will attend a Fall Retreat.
  • Scholars are selected by the Foundation Scientific Advisory Board and peer reviewers selected from past Forbeck Scholars.

General Program

The outline below illustrates a typical program schedule. You will receive a complete schedule, including speaking times, the Thursday the meeting starts.

Arrival Day
1:00 PM Arrivals
6:00 PM Cocktails (opt'l)
7:00 PM Dinner
Meeting Day 1
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Meeting Day 2
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Departure Day
7:00 AM Breakfast
8:00 AM Departures

Frequently Asked Questions

Below are some of our most Frequently Asked Questions. If you have something new to ask, please feel free to contact us.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • Frequently airport transfer is provided by volunteers. Please be patient on receiving this information. Airport transfer will be sent out prior to arrival.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.

Forum Participants

Nabeel
Bardeesy
,
PhD
Massachusetts General Hospital
Bryce
Carey
,
PhD
Rockefeller University
John
Denu
,
PhD
University of Wisconsin
Andrew
Dillin
,
PhD
University of California, Berkeley
Lydia
Finley
,
PhD
Memorial Sloan Kettering Cancer Center
Christian
Frezza
,
MSc, PhD
University of Cambridge
Lucy A.
Godley
,
MD, PhD
Northwestern University
Russell
Jones
,
PhD
Van Andel Institute
William G.
Kaelin, Jr.
,
MD
Dana-Farber Cancer Institute
Mei
Kong
,
PhD
City of Hope
Jason
Locasale
,
PhD
Duke University
Oliver G.
McDonald
,
MD, PhD
Vanderbilt University
Jordan
Meier
,
PhD
National Cancer Institute
Joshua D.
Rabinowitz
,
Princeton University
Martine F.
Roussell
,
PhD
St. Jude Children's Research Hospital
Paolo
Sassone-Corsi
,
PhD
University of California, Irvine
Benjamin
Tu
,
PhD
UT Southwestern
Karen
Vousden
,
PhD
Crick Institute

Forum Scholars

No Scholars attended this meeting