UMass Chan Medical School
Cancer Chromosome Genetics
building cancer genomes in the lab.
We use the principles of systems genetics applied to tumor copy number landscapes to dissect the driving forces behind tissue-specific tumor aneuploidy patterns.
What's the best way to study a large chromosomal aberration like an arm-level amplification to understand it's role in cancer? Make it in the lab and compare to isogenic diploid cells!
So that's exactly what we do, using classical forward genetic dogma to get us there! By screening libraries of aneuploid mutants derived from normal diploid epithelial cells for fitness, then evolving many different clonal lineages in vitro, we obtain the same kinds of chromosomal aberrations observed in cancer (remarkably even at similar frequencies seen in patients!).
Oh, and it's tissue-specific: mammary epithelial cells in our system select breast cancer chromosomal abnormalities, while renal cells select renal cancer chromosome profiles.
We use these lab-grown tumor-like genomes (which are not complicated by other background mutations) in comparative genomic & transcriptomic analysis with human tumors to generate hypotheses about the functions (and more generally the 'phenotypes') of the most frequent tumor-associated chromosomal abnormalities like +1q and +8q.
The ultimate goal is to utilize this deep phenotypic profiling to target chromosomal aberrations therapeutically.
Figure: Genomes of aneuploid human mammary epithelial cell clones undergoing selection in vitro over 40 population doublings
rare cancer fusion oncogene network.
Sometimes chromosomal translocations formed from intragenic breaks generate potent fusion oncogenes. The most prevalent among them being TMPRSS2--ERG, which occurs in ~50% of prostate cancers.
Interestingly, many rare cancers are characterized by recurrence of specific fusion oncogenes. Sometimes partner choice is strict; almost every case will have the same fusion between the same two genes. Other rare cancer types display strict choice of only one gene and promiscuous choice of its fusion partner. Yet others "mix and match" partners from within a looser network of genes (which usually are functionally or structurally related).
What drives these specific fusion/disease interactions? An "oncogenic gatekeeper" model would propose that these fusions are pro-tumorigenic events only in certain cell types. A "location opportunity" model would propose that breakpoints and fusions are more frequently generated in certain cell types (due possibly to levels of transcription, replication timing, 3D-organization, etc) leading to opportunity for their selection during tumorigenic transformation.
To begin to answer the tissue-specificity question of fusion oncogene function in rare cancers, we have generated a rare cancer fusion oncogene ORF (open reading frame) library.
Figure: A comprehensive Rare Cancer Fusion Oncogene Network. Nodes indicate genes, edges indicate fusions, colors indicate disease sites of origin.
Emma V. Watson, PhD
Emma received her B.S. in Biophysics from UConn and her Ph.D. in Biomedical Sciences from UMass Chan Medical School. She was a Damon Runyon Postdoctoral Fellow (Suzanne and Bob Wright Fellowship) in Stephen J. Elledge's lab at Harvard Medical School/Brigham and Women’s Hospital, then an Instructor/Associate Geneticist. She re-joined UMass Chan Medical School as an Assistant Professor in 2022 in the Department of Systems Biology .
Emma is interested in utilizing high-throughput genetic screens to study chromosomal aberrations in tumorigenesis.
She did not star in any of the Harry Potter franchise films.
Rayna received her B.A. in Integrative Physiology from the University of Colorado at Boulder. She is currently writing her thesis at Boston University in pursuit of an M.S. in Medical Sciences.
Rayna is interested in developing targeted therapeutics for tissue-specific copy number profiles in cancer.
Abdulrazak received his B.S in Biotechnology from Worcester State University in 2022. His interests include tissue culture and cell biology.
Outside of the lab he enjoys soccer (favorite team: Tottenham Hotspurs), book writing, and beating his brothers in Mario Kart. He loves to travel and can speak a bit of French and Arabic (Moroccan) and is learning Japanese.
Affiliate Lab Members
Doge in Residence
Resident therapy doge/crypto advisor/snacko taster
13 year old Shiba Inu. Won't help with your experiments. Will help with your lunch. Very good chonki boi.
Cat in Residence
Resident mouse killer/inter-dimensional traveler/will judge you.
Agent of entropy. Will "help" with unpacking, loves cardboard boxes.
Official Lab Portrait
Family Photo: L to R: Arshia Kaur (rotation student), Abdulrazak Frederick, Emma Watson, Faith Keller (rotation student), and Rayna Magesh.
We did a thing!