Join the lab

ecDNA are circular pieces of DNA that carry amplified oncogenes. They have no centromeres, so there is no obvious reason they should survive cell division, and yet they reach daughter nuclei reliably. We showed that they hitchhike on mitotic chromosomes, and that the connection depends on transcription continuing through mitosis at a time when most of the genome has gone quiet. Block that transcription and ecDNA come loose, spill into the cytosol, and reintegrate into chromosomes as long tandem arrays.

That work opened three questions.

What makes the physical connection. We know ecDNA contact the ends of mitotic chromosomes and we know transcription is required. We do not know what sits between them.

What proteins are found with ecDNA, and what they do there. ecDNA occupy a distinct protein environment inside the nucleus. Identifying its occupants is the first step to knowing which ones matter.

How ecDNA reintegrate into chromosomes. When ecDNA are released they can insert back into the genome as tandem arrays. This is a different route to oncogene amplification and how it happens is unknown.

APOBEC3A is one of the largest sources of point mutations in human cancer, and it is almost undetectable in most measurements of tumors. We resolved part of that contradiction by showing the enzyme works in bursts, switching on inside a rare and short-lived cell state that resembles squamous differentiation, and that cancer drugs push cells into the same state.

Two questions follow.

What controls entry into that state. A squamous transcription factor is involved. What else gates the door is open.

Why APOBEC3A and not APOBEC3B. Deleting APOBEC3A removes the mutational signature in most settings and deleting APOBEC3B often does not, which was unexpected given that APOBEC3B is far more abundant. Where each one matters, and why, is unsettled.

When chromosomes are mis-segregated, DNA ends up in the cytoplasm, where the cell reads it as a danger signal. The enzyme TREX1 degrades that DNA and keeps the alarm from sounding, which is one way tumors stay invisible to the immune system. We found that TREX1 has to be anchored to the ER to do it, and that a protein barrier assembles around the exposed DNA which TREX1 must get past.

Two questions follow.

How TREX1 gets past the barrier. ER anchoring lets it bypass a barrier that blocks other DNA-binding proteins. The mechanism is unknown.

Whether autophagy factors participate. Autophagy-related proteins may contribute to how TREX1 shuts down cGAS-STING signaling. This project tests whether they do.

The structure is layered, so that people can have as much or as little contact with me as they need.

The whole lab meets on Tuesdays at one o'clock, alternating between data presentations one week and a journal club the next. Everyone presents in each of these once or twice a year. Once a month we split into smaller meetings by topic, one on innate immunity and one on cancer genome evolution. Also once a month is meeting week, when senior members sit down with me one on one. Everyone is in front of me at least twice a month by default. On top of that I post office hours every week, and my door is open outside them.

Rotation students meet with me weekly.

I also run a separate journal club for people new to the lab, covering the classic papers in the field that a lab-wide journal club does not get to. It is small and it is demanding. Depending on how many people are enrolled in a given year, you present every week or every other week. It is the closest thing we have to a bootcamp for the candidacy exam, and the people who have been through it say it was worth it.

PhD students are admitted through their graduate program rather than by me directly. If you want to rotate here, you first need to be admitted to one of these:

MD-PhD students are welcome to rotate.

If you are already in one of these programs, email me at maciejoj@mskcc.org.

Rotations vary in length depending on your program. Sometimes a rotation student takes a project of their own. More often you will work with a senior postdoc or graduate student on part of theirs.

Two things are expected of every rotation student. You will present at the lab-wide journal club, and you will present your rotation results at lab meeting.

Email me at maciejoj@mskcc.org with your CV and a cover letter. The cover letter should cover what you have worked on, why you want to work in this lab specifically, and where you want your research to go in the long run. You do not need to propose a project, though you are welcome to. Three references, later in the process.

What I am looking for. Ambitious people who are not afraid of hard problems. People who can run independently but stay engaged with the rest of the lab, because the best colleagues here make everyone else's science better. I want people who make interesting discoveries and lift the work of the people around them at the same time.

Postdocs in this lab compete successfully for external funding. Fellowships held by current and former members include the Jane Coffin Childs Memorial Fund, the Eliasoph Postdoctoral Research Fellowship, the Monahan Fellowship from the JLM Fund, and the Center for Experimental Immuno-Oncology Fellowship. Graduate students in the lab currently hold two NIH F31 awards.

If you are applying from outside the United States, MSK sponsors J-1, H-1B, O-1, TN, and E-3 status depending on circumstances. MSK Immigration Services has the details, and general information for postdocs at MSK is here.

Technicians here are treated as early-stage PhD students. Roughly seventy percent of your time goes to your own project. You present at lab meeting and at journal club, and you take part in the journal club I run for new members of the lab. The remaining thirty percent is keeping the lab running, which means ordering, stocking, and equipment.

Three former technicians from this lab are now PhD students at Weill Cornell BCMB, Rockefeller University, and the Institut Curie.

I ask for a two-year commitment.

Email me at maciejoj@mskcc.org with your CV and a short note about what you want to do next.

Everyone presents at lab meeting, and everyone's voice counts in it.

I encourage everyone to travel to at least one conference a year.

People have their own projects and also collaborate across them, which is why most papers from the lab have several people on them.

The lab runs two Nikon CSU-W1 SoRa spinning disk microscopes, an additional spinning disk, and a widefield DeltaVision. We also draw on MSK's core facilities, which cover sequencing, proteomics, flow cytometry, and more.