Biomolecular Condensates in Cancer
Forum Chairs
Forum Description
Large-scale cytological changes are a classical hallmark of cancer, although the molecular etiology of these changes has historically been poorly understood. A cell can be organized through membrane-bound organelles such as endoplasmic reticulum and Golgi, or through membrane-less biomolecular condensates such as nuclear bodies and stress granules. While membrane-bound organelles are well-studied, the biology of membrane-less biomolecular condensates is less well-understood. It has recently been found that biomolecular condensates form through phase separation - a demixing phenomenon in which the associated macromolecular components form a dense liquid-like assembly. In addition to large well-defined membrane-less organelles, there exist a growing number of examples in which smaller biomolecular condensates mediate key biological processes. Of particular recent interest, much of the transcriptional machinery appears to consist of biomolecular condensates. The meeting is timely since the field of biomolecular condensates in various aspects of biology has grown exponentially in recent years, and the roles of biomolecular condensates in diseases such as cancer are just beginning to be uncovered.
Misregulation of biomolecular condensates is intimately linked to cancer. For example, both PML bodies and the nucleolus are classic membraneless organelles, and both show massive morphological changes in transformed cells, a result that can now be rationalized in terms of changes to the phase behaviour associated with the underlying components. A number of specific cancers are directly linked to proteins we now know can form biomolecular condensates. The FET family proteins are a collection of RNA binding proteins that contain large unstructured low-complexity domains (LCDs). These LCDs are necessary and su cient to drive phase separation, and in a number of different cancers these LCDs translocate to oncogenic DNA binding domains, driving malignancy. A working model suggests the formation of LCD-mediated assemblies at the associated genetic loci recruits transcriptional machinery, driving unfettered gene expression. While the FET proteins lead to malignancy through oncogenes, cancer-associated mutations in the tumor suppressor SPOP disrupt its normal ability to phase separate, demonstrating that both gain-of-function and loss- of-function mutations are possible.
At the level of gene regulation, super-enhancers are biomolecular condensates that occupy specific loci on the genome and drive high-level constitutive transcription. Recent work suggests that super-enhancers form through phase separation, and that their formation at oncogenes may be a common mechanism through which transcriptional upregulation occurs in transformed cells.
Taken together, there is a growing body of work suggesting biomolecular condensates play strong roles in cancer. This is of particular interest from a therapeutic stand-point as previously ‘untreatable’ malignancy should become vulnerable through a better understanding of the molecular basis of their origins. The goal of this timely Forbeck meeting is to bring together cancer-focused medical scientists, biophysicists and cell biologist in an intimate multi- disciplinary environment to generate ideas on how study of this novel eld can lead to novel treatments for cancer.
Forum Summary
We had a very productive Forbeck Forum on Biomolecular Condensates in Cancer, thanks to the generous support by the William Guy Forbeck Research Foundation. Biomolecular condensates are membrane-less organelles in cells that can concentrate specific proteins or nucleic acids and perform specific functions. The attention to them has grown rapidly in recent years, since they were found to be involved in a myriad of cellular processes, with their dysregulation linked to diseases such as neurodegenerative diseases and cancer. While the importance of biomolecular condensates in cancer is emerging, a lot remains unknown. This timely meeting was chaired by Drs. Tanja Mittag (St. Jude Children’s Research Hospital), Danfeng Cai (Johns Hopkins University), and Alex Holehouse (Washington University in St. Louis). We convened the experts in this nascent field, combining expertise from biophysicists, cell biologists, and clinicians of all career stages and from institutes throughout the world. The forum also welcomed two new Forbeck Scholars: Jeong Hyun Ahn and Aravinthkumar Jayabalan.
We focused on understanding the following questions: 1) How do we define biomolecular condensates? 2) What is the molecular grammar of forming condensates in cancer? 3) How do condensates organize DNA? And 4) How do condensates lead to cancer?
The Forum started with provocative discussions on the definitions of biomolecular condensates. The participants settled on that they are “non-stoichiometric assemblies of biomolecules”, removing the need to formally demonstrate phase separation inside the cell. We also discussed unpublished research testing the necessity of phase separation in protein function, by finding mutations that can alter protein solubility but not binding. Throughout the forum, there were excellent talks on fusion oncoprotein phase separation, nuclear transcription hubs, stress granules, and in vitro reconstitution of DNA repair foci. The forum captured the state-of-the-art in the field and the level of discussion was terrific.
The participants acknowledged the difficulties of testing components and functions of biomolecular condensates in cancer, in part due to the lack of tools to study them in the cellular context. On this matter, we discussed the capability of novel and powerful tools such as proximity ligation-based proteomics, single molecule tracking, and large-scale computational analysis.
The format for Forbeck Forums is highly conducive to stimulating discussion and critical evaluation of ideas. All participants enjoyed the meeting very much. The interactions in the meeting also fueled new collaborations, including those among computational biologists and cell biologists, cancer researchers and biochemists.
Venue & Travel Information
Travel Forms
Travel forms are due 30 days prior to the start of the meeting to allow enough time to plan transportation.
The San Diego International Airport (SAN) is the preferred airport as it is only 30 minutes from the meeting location.
- Arrivals - Thursday at 1 PM, 3 PM and 5 PM
- Departures - Sunday at 10 AM, 12 PM and 2 PM
Travel Policy
Please familiarize yourself with our policies and procedures for travel. We truly appreciate you taking the time to participate in this forum. 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 forum. 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 forum 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 forum.
- Speaker agenda is not sent out prior to the forum. It will be provided upon arrival in the forum 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 forum. Please no children.
What the Foundation Pays
Accommodations and meals are provided by the foundation during the forum. Airfare will be covered only if booked in accordance with our policy and only up to the amount in which you were approved for. The Foundation will also cover airport transportation on the forum 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.
- Note we do not cover upgrades, changes, late bookings, etc.
- Flights must be booked at least 30 days prior to the forum 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 forum. 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.
Forum Structure
The structure of the forum 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 2 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 forum is relatively short, so please be familiar with papers received prior to arrival.
- It is very important that you commit to all sessions of the 2 days of the forum.
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 forum starts.
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 forum. 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 forum.
- 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.
- 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.