Mapping the developing cortex, red meat's molecular links to colorectal cancer, using proteomics to advance immunotherapy, and more
Research Roundup: June 25, 2021
Welcome to the June 25, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
A cerebral cinema
The cerebral cortex comprises a rich diversity of cell types that form in a series of tightly controlled steps. The molecular logic behind this dynamic and complex process, though, has been a mystery. Using single-cell RNA and chromatin data, Daniela DiBella, Ehsan Habibi, core institute member (on leave) Aviv Regev, institute member Paola Arlotta, and colleagues in the Stanley Center for Psychiatric Research and the Klarman Cell Observatory produced a developmental map of a region of the mouse cortex: a molecular movie that follows cortical development from the embryo to shortly after birth, reconstructs the cortex's cellular lineages and spatial organization, and captures a unique view of how cortical development is regulated. Learn more in Nature and a Harvard/Broad news story.
A mechanistic link between red meat and colorectal cancer
A new study published in Cancer Discovery has identified a new mutational process in colorectal cancer and linked it to high red meat consumption and increased colorectal cancer-related mortality. Carino Gurjao, Yvonne Li, Liam Spurr, Brendan Reardon, group leader Andrew Cherniack, associate member Eliezer Van Allen, associate member Shuji Ogino, associate member Marios Giannakis, and colleagues of the Dana-Farber Cancer Institute and the Cancer Program performed whole-exome sequencing of colon tissue from 900 patients with colorectal cancer. They found evidence that alkylating damage-related mutations in cancer-related genes were associated with a diet high in red meat. These results could lead to better prevention, diagnostic, and treatment options for colorectal cancer. Read more in a Dana-Farber Cancer Institute Press Release and coverage from Genetic Engineering & Biotechnology News.
A STAGgering sarcoma study
Patients with STAG2-mutated Ewing sarcoma have a higher rate of metastatic disease and worse outcomes than those without the mutation. A team including Biniam Adane, Gabriela Alexe, associate member Brian Crompton of Dana-Farber Cancer Institute and the Cancer Program, and institute member Kimberly Stegmaier explored the role of STAG2, an element of the cohesin complex, in gene-regulatory architecture. They knocked out STAG2 in Ewing sarcoma cell lines, which triggered transcriptional changes that modulate EWS/FLI1 oncogene, migratory, and neurodevelopmental programs. Loss of STAG2 enhanced the metastatic potential of Ewing sarcoma xenografts. Appearing in Cancer Cell, the work demonstrates that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype.
CD8 T cell dysfunction in disease states is not so different after all
In autoimmune conditions, cancer, and chronic infections, CD8+ T cells are chronically exposed to antigens, causing dysfunction. But in autoimmune conditions, CD8+ T cells become overactive, whereas in cancer and chronic infection, they become suppressed. Jenna Collier, institute member Arlene Sharpe of the Immunology Program, and colleagues review how these seemingly opposite CD8+ T responses may have similar underlying molecular mechanisms at functional, transcriptional, and epigenetic levels. The authors highlight the importance of understanding the similarities and differences in CD8+ T cell dysfunction in different disease states for developing effective therapies. Read more in Nature Immunology.
Promoting persistence in STEM research careers
Diedra Wrighting (now at Northeastern University), Marlina Duncan (now at UMass Medical School), Gisselle Vélez-Ruiz, associate director of Broad’s Diversity, Education and Outreach office (DEO), institute scientist and DEO founder Bruce Birren, and colleagues at UMass Boston recently developed a semester-long undergraduate course that teaches concepts and strategies that contribute to STEM persistence, particularly for students from underrepresented groups in STEM. This was based on a curriculum developed by DEO for its Broad Summer Research Program. They taught the course at UMass Boston, and report in CBE-Life Sciences Education that students in the course learned in all three of the emphasis areas: scientific communication; maximizing the effectiveness of research mentoring relationships; and navigating scientific culture and its interactions with multiple social identities.
Role of proteomics in developing future immunotherapies
Even with the tremendous success of immunotherapies, it is still difficult to select targets for such treatments. Human leukocyte antigen class II peptides (HLA-II) represent a class of potential immunotherapy targets and biomarkers. In a review in Molecular and Cell Proteomics, Hannah Taylor, institute scientist and senior director of Proteomics Steven Carr, senior research scientist Jennifer Abelin, and colleagues in the Proteomics Platform explain how mass spectrometry analysis will enable a better understanding of the molecular basis of HLA-II and its role in disease progression. The authors also highlight a subset of knowledge gaps and challenges that HLA-proteomics technologies could address and help in the development of personalized immunotherapies across multiple diseases.
Assessing similarity between cancer cells and tumors
Immortalized cancer cell lines are a cornerstone of cancer research, but some lines may be too different from tumors to be helpful models. Associate member Chris Sander of the Cancer Program, Augustin Luna, and colleagues have developed TumorComparer, a computational method that compares molecular and genetic profiles in cell lines using different weights for features of interest. The team demonstrates their approach in nearly 600 cell lines and 8,000 tumors across 24 cancers. In the future, TumorComparer could help stratify patients for clinical trials as well as in more personalized medicine, and it is available now as an R package and a web application. Read more in Cell Reports Methods.
A more detailed profile of single cells
In Nature Biotechnology, a team led by Caleb Lareau, Leif Ludwig, associate member Vijay Sankaran in the Program in Medical and Population Genetics, Aviv Regev, and colleagues from the New York Genome Center and Osaka University describes two new single-cell analysis techniques to more precisely define cell types and cell states. ASAP-seq and DOGMA-seq enable measurement of chromatin accessibility, gene expression, and protein levels in single cells, with optional detection of mtDNA genotypes. The team used this multimodal approach to profile bone marrow cells, charting the complex interplay of gene and protein regulatory layers. Read more in GenomeWeb and a tweetorial from Lareau.