Studying cancer evolution needs multi-region or single cell seq for phylogenetics, right? Amazingly (I think!) we found single-sample bulk methylation suffices, via analysis of "fluctuating methylation". In @nature.com today led by brilliant @calumgabbutt.bsky.social www.nature.com/articles/s41...
Goldschmidt's hopeful monsters in cancer: single cell DNAseq shows whole genome doubling (WGD) is an ongoing and frequent mutational process in ovarian cancer. www.nature.com/articles/s41... beautiful work from @sohrabshah.bsky.social and team
We are assembling an exceptional multidisciplinary team, and we are currently hiring! Let's connect: vazquezgarcialab.mgh.harvard.edu [13/13]
If you are excited by this kind of work, I am building my new lab at Massachusetts General Hospital, Harvard Medical School, and the Broad Institute. 🧬🔬 @mgbresearch.bsky.social @harvardmed.bsky.social @broadinstitute.org #NewPI #AcademicTwitter [12/13]
Thank you also to the entire MSK SPECTRUM team @mskcancercenter.bsky.social. Deeply grateful to @cycleforsurvival.bsky.social, OCRA, CDMRP and @cancergrand.bsky.social for their generous support. [11/13]
This study reflects the collective efforts of an extraordinary team. I am especially thankful to @sohrabshah.bsky.social for his guidance and mentorship, and to Andrew McPherson, Matt Myers, Duaa Al-Rawi, and Matthew Zatzman for an outstanding collaboration. [10/13]
For a broader perspective on the therapeutic relevance of our findings, please check out the @nature.com News & Views by Nikki Burdett and Elizabeth Christie, which discusses WGD as a potential clinical target:
www.nature.com/articles/d41... [9/13]
For a succinct summary of our work, please see Safia Danovi’s research highlight in @natgenet.nature.com, capturing the key findings and implications of WGD dynamics in HGSOC:
www.nature.com/articles/s41... [8/13]
So what is the big picture? Our work redefines WGD as a dynamic mutational process that promotes genomic diversification and immune escape. WGD status may serve as a new biomarker to guide therapies like PARP inhibitors and inform the development of future targeted agents. [7/13]
How do WGD tumors tolerate instability and evade immune sensing? WGD alters cell state: it delays G1/S, represses STING and IFN signaling, and decouples immune activation from chromosomal chaos despite abundant cytosolic DNA from ruptured micronuclei. [6/13]
Despite elevated chromosomal instability, WGD-high tumors exhibit tolerance to progressive karyotypic disruption, favoring gradual, post-WGD copy number losses. This supports a model where WGD promotes diversification via genomic remodeling. [5/13]
WGD was linked to elevated chromosomal instability: copy number alterations, missegregations, and ruptured micronuclei. We quantified these rates at single-cell resolution, using scWGS + phylogenetic analysis and multiplexed IF + deep learning-based image segmentation. [4/13]
We found that WGD is not a static or historical event. Nearly all tumors exhibited mixtures of 0×, 1×, and 2× WGD cells. Several tumors showed parallel WGD events in distinct subclones, while others displayed the emergence of new WGD clones late in evolution. [3/13]
To answer this, we generated single-cell whole-genome sequencing (scWGS) data from >30,000 tumor cells across 41 patients with high-grade serous ovarian cancer (HGSOC). We integrated this with multiplexed immunofluorescence (IF) and single-cell RNA-seq data. [2/13]
Thread 🪡:
WGD is common in human cancer and has been linked to poor prognosis, drug resistance, and metastatic dissemination. But when does WGD occur? Is it a one-time event or an ongoing process during tumor evolution? And what are its phenotypic consequences? [1/13]
Whole-genome doubling (WGD) occurs in ~30% of solid tumors and is linked to poor outcomes. Is it a one-time event or an ongoing mutational process?
In our new @nature.com paper now in print, we show WGD continuously shapes tumor evolution and immune evasion.
www.nature.com/articles/s41...
We have two #postdoc positions open to join my team at @ebi.embl.org in beautiful Cambridge!
We are a mission-driven, highly collaborative and dynamic team located at the Wellcome Genome Campus, one of the most exciting hubs in the world focused on biomedical research 👇
The stomach is an organ unique in its function, environment and exposures. How does this affect the mutations that normal cells in the stomach acquire? What does this reveal about the origins of stomach cancer? These questions and more in our @nature.com paper:
www.nature.com/articles/s41...
Thank you!
Thank you!
We are seeking exceptionally curious and driven scientists at all stages (postdocs, grad students, undergraduates, research associates) – both computational and experimental! Please reach out if you have an interest in joining, collaborating, or have advice for a new PI! (7/7)
I excitedly look forward to joining the world-class science and outstanding community at MGH Pathology, MGH Cancer Center and Broad, who have already made me feel most welcome on my first day. (6/7)
My deepest gratitude goes to my exceptional mentors, colleagues, collaborators, sponsors, family and friends. 🙏 @mskcancercenter.bsky.social @mskeducation.bsky.social @columbiauniversity.bsky.social @sangerinstitute.bsky.social @cancergrand.bsky.social @wellcometrust.bsky.social (5/7)
Our ultimate goal is to impact human health and clinical care for patients, leveraging our understanding of cancer trajectories to enable biomarkers and therapeutic strategies that anticipate and overcome tumor progression. (4/7)
We will focus on quantitative approaches to study cellular dynamics in tumors, combining new high-throughput genomics and AI/ML approaches with large clinical datasets and experimental models. (3/7)
Our lab will aim to discover fundamental principles of clonal evolution in cancer, from the emergence of malignancy to its evolution towards lethal and resistant disease. (2/7)
New year, new beginnings! I am absolutely delighted to share that I have joined Harvard Medical School, Massachusetts General Hospital and Broad Institute to start my research group in Boston in January 2025! 🎉🧬🔬 #NewPI #AcademicSky #NextChapter (1/7)
Thanks for creating this! I would love to join if possible.
Thanks for creating this! I would love to join if possible.
Thanks for creating this! I would love to join if possible.
