Molecular and Cellular Oncology
Molecular and Cellular Oncology Program
The Molecular and Cellular Oncology Program (MCO) organizes an outstanding group of researchers whose work provides insights into gene expression regulation and its deregulation in cancer, the cellular response to genomic insults, the molecular structure of cancer-relevant proteins, and new signaling processes driving tumor growth.
Our researchers collaborate with other programs to translate their basic discoveries into better tools for cancer prevention, diagnosis, and treatment.
We develop these novel technologies and approaches:
- Synthetic lethal shRNA screens in human cells to identify pathways conferring resistance to targeted therapies
- New phospho-proteomics approaches to elucidate oncogenic protein kinase signaling pathways
- Cutting-edge metabolomics approaches to uncover weaknesses in cancer cells that can be exploited to therapeutic advantage
- Advanced crystallographic, electron microscopy, and NMR studies of protein structure
Scientific Goals:
Research in the MCO program is directed toward elucidating fundamental biological processes in cancer biology and translating these basic discoveries into better tools for cancer prevention, diagnosis, and treatment through collaborative research with other CU Cancer Center programs.
Focus Groups
Maintenance of Genomic Integrity - Investigators work on genomic re-arrangements and retro-transposition; DNA replication, repair, and the DNA damage cell cycle checkpoint; mutagenesis and the response to ionizing irradiation, telomerase, and DNA end-repair.
Gene Expression and Biomarkers - Investigators work on specification of cell fates; nuclear acceptors of signaling and environmental pathways; fundamental mechanisms of transcriptional regulation; the interplay between transcription and RNA processing, cancer survival pathways; and the regulation of protein synthesis and proteomic identification of cancer biomarkers that result from altered gene expression.
Cancer Structural Biology - Investigators delineate the molecular structure of RNA, DNA-binding proteins, signaling molecules, and oligopeptides using biophysical techniques, cryo-EM, NMR, and X-ray crystallography.
Programmatic Goals:
- Promote career development for junior members and trainees
- Maintain a diverse, equitable, and inclusive climate for all members
- Stimulate inter- and intra- program collaborations
- Facilitate access to new technologies and resources
- Create forums for scientific exchange and discussion
- Discover basic cancer processes that can be collaboratively translated to the clinic
- Generate improved understanding and treatment of cancer types relevant to Colorado populations
Incorporating Diversity and Equity into Basic Cancer Research
The 2021 Molecular and Cellular Oncology (MCO) annual retreat focused on how researchers who are studying molecular mechanisms in cancer could incorporate the issues of high relevance to the catchment area and health disparities that are driven by race, ethnicity and socioeconomic status.
The keynote speaker, Anne-Kathrin Eisfeld, MD, from Ohio State University, presented on racial and socioeconomic disparities in survival of adult AML patients. The retreat also featured Chris Gignoux, PhD, presenting about the Colorado Center for Personalized Medicine biobank, Evelinn Borrayo, PhD, presenting on disparities in cancer patients in Colorado, Adam Green, MD, presented his work on disparities in CNS cancer patients in the US and CO, and Sean Davis, MD, PhD, presented related Campus Resources. Alexis Zukowski, a postdoc trainee in an MCO lab, discussed how she is customizing a new chromatin-based assay for low-cost biomarker detection to make it more applicable to underserved populations.
Following the presentations was a discussion session with our panel of experts. This brainstorming session produced many good ideas for how MCO can support researchers who want to incorporate race/ethnicity information into their work with bio-samples such as cell lines. One of the most insightful comments was from Sean Davis, MD, PhD, who told us that race/ethnicity information could be inferred from public (GEO) ChIP seq or RNAseq datasets.
MCO has compiled some resources to encourage Cancer Center members to consider diversity and disparity when designing their experiments. We are also spearheading efforts to provide funds for Cancer Center members to gather ancestry information of their biologic resources, so stay tuned for funding announcements!
Colorado Biobank Portal
The portal supports queries across ~1,300 genome-wide association studies using ICD-derived PheCodes. The GWAS runs were performed on full TOPMed imputation and involve ~50 million sites along the genome in our currently-genotyped freeze of ~34,000 CCPM participants.
Here is what you can do with the data:
Query by phenotype: Most phenotypes will autocomplete in the search bar. The mapping of phenotypes from ICD codes is available at https://phewascatalog.org/
- Query by chromosome and position: The Portal shows SNP density in your region.
- Query by gene or transcript: The portal shows all SNPs annotated to a gene as a table and a plot with variants in or near coding regions.
- Do a phenome-wide association study (PheWAS) on the fly by querying a SNP of interest.
This portal is intended to provide preliminary analyses to support grant proposals and generate hypotheses. If you are interested in accessing the tool, register at https://ucdenverdata.formstack.com/forms/cbe_user_signup_ccpm.
Articles that explain the need to consider genetic ancestry and sex
- Awareness is created by visibility talks about the need to have cell lines that represent human populations equally.
- Misclassification of some cancer cell lines with regard to their genetic ancestry.
- Ancestry matters: Building inclusivity into preclinical study design.
- The need to use diverse cell lines in drug development.
Papers that address the genetic background of common cell line models.
- Carrot-Zhang et al., Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer. Cancer Cell 2020 May 11;37(5):639-654.e6. PMID: 32396860
- Ghandi et al., Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature volume 569, pages503–508 (2019). PMID: 31068700 Supplementary Table 1
- Dutil et al., An Interactive Resource to Probe Genetic Diversity and Estimated Ancestry in Cancer Cell Lines. Cancer Res 2019 Apr 1;79(7):1263-1273. PMID: 30894373
- Kessler et al., Ancestral characterization of 1018 cancer cell lines highlights disparities and reveals gene expression and mutational differences. Cancer 2019 Jun 15;125(12):2076-2088. PMID: 30865299
- Yuan et al., Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers. Cancer Cell. 2018 Oct 8;34(4):549-560.e9. PMID: 30300578
Online resources with ancestry/sex information for biologics:
UCCCReporter: Cell line ancestry for common cancer cell lines
https://seandavi.github.io/UCCCReporter/reference/cell_line_ancestry.html
COSMIC (catalog of somatic mutations in cancer)
https://cancer.sanger.ac.uk/cosmic
Cellosaurus, a knowledge resource on cell lines.
https://web.expasy.org/cellosaurus/
Colorado Central Cancer Registry
https://cdphe.colorado.gov/center-for-health-and-environmental-data/registries-and-vital-statistics/colorado-central-cancer
Funding
NIH/NCI has several active calls for Basic Research in Cancer Health Disparities.
‘This Funding Opportunity Announcement (FOA) encourages grant applications from investigators interested in conducting basic, mechanistic research into the biological/genetic causes of cancer health disparities.’
https://grants.nih.gov/grants/guide/pa-files/PAR-21-322.html (RO1)
https://grants.nih.gov/grants/guide/pa-files/PAR-21-323.html (R21)
https://grants.nih.gov/grants/guide/pa-files/PAR-21-324.html (RO3)
Think Outside the Box
to Help Colorado Cancer Patients and Win $2000!
Open to all MCO Lab Trainees!
- Molecular and Cellular Oncology Program is looking to reward trainees who can think of creative ways to connect their research to the people of Colorado
- Submit one idea on how research in your lab (need not be your own research) can be applied to better understand cancers prevalent in Colorado* or to serve the specific demographics of people of Colorado, especially populations that are underserved/non-majority**.
- This is basically a Letter of Intent (LOI). You are coming up with ideas at this point but are not necessarily committed to the proposed project.
- We are looking for outside-the-box ideas. For example:
- Your lab studies folate metabolism. You use CCPM data to identify a variant in an enzyme in this pathway that is prevalent in Colorado Hispanic population, and propose to study its effect on folate biosynthesis.
- You hypothesize that loss of function variants in a gene of interest are linked to breast cancer in Colorado populations. You can request genotypes linked to this gene in the CCPM cohort and explore association with cancer in patients of various races/ethnicities. You can then propose to CRISPER a variant that shows association into your favorite cell line to study the effect on drug resistance.
- You are interested in performing genome-wide association (GWAS) study for a novel clinical phenotype (e.g., a subset of cancer patients that do not respond to a specific therapy). You can them propose a study as described in 2.
- You study DNA damage responses (DDR). You can identify an environmental pollutant that CO populations are exposed to. You can propose to study the effect of that pollutant in your DDR assays. Such a project does not utilize CCPM but that is fine.
- Upload your 1-page proposal here by November 21, 2022. The Contest will be discussed at the MCO Retreat and winners announced at a later date.
- Winners will receive $2000 to use towards career development activities of their choice (conference travel, workshop attendance, lab /computer equipment purchase, etc.)
- Who is eligible: students and post-docs in MCO labs (if you are unsure, ask your PI if they are an MCO member).
* cancers of high relevance to Colorado: colorectal, melanoma, lung, breast, pediatric cancers
** underserved populations in CO such as rural, Hispanic & pediatric (you may address one or more)
#CCPM has genotyping (SNP) information from ~ 34,000 CO patients that comprise of 50 million variants. This database is useful to study common germline variants and their association with disease. It also has whole exome data from ~ 45,000 CO patients. Whole exome data allows studying genetic variation with the coding sequences of genes of interest. If your idea includes a request of genetic data from the CCPM Biobank, please reach out to Nikita Pozdeyev to discuss feasibility.
Questions? Email tin.su@colorado.edu or patricia.ernst@cuanschutz.edu
Molecular and Cellular Oncology Leadership
Patricia Ernst, PhD
Program Co-Leader
Dr. Ernst is the Co-Leader for Molecular and Cellular Oncology (MCO) Program. She is a Professor in the Department of Pediatrics, Heme/Onc/BMT section. Her research program focuses on childhood leukemia, normal hematopoiesis and epigenetic factors regulating these processes. She has been continuously funded for over 17 years by grants from NIDDK, NHLBI, NIAID, OD and NCI. In addition to her role as program co-leader, Dr. Ernst serves as Associate co-Director of the Medical Scientist Training Program for the University of Colorado and recently rotated out of the Presidency of the International Society for Experimental Hematology. She serves on editorial boards of Blood, Journal of Experimental Medicine and Frontiers in Immunology. As program co-leader, Dr. Ernst serves as the site leader for the University of Colorado Anschutz Campus and a liaison for training programs at the University of Colorado Denver. Together with MCO co-leader Dr. Su she works to coordinate all aspects of MCO planning, development, execution, and evaluation.
Tin Tin Su, PhD
Program Co-Leader
Dr. Su is the Co-Leader for Molecular and Cellular Oncology (MCO) Program. She is a Professor in the Department of Molecular, Cellular and Developmental Biology at the University of Colorado, Boulder. She is an experienced investigator in the field of radiation biology of Drosophila and human cancer models. She is currently the PI of R35GM130374 and is one of two PIs for the NCI SBIR phase II contract 75N910196C00038. In addition to her role as program co-leader, Dr. Su serves as the Director of Graduate Student Affairs in her home department. She is the current President of the Drosophila Board and serves as the chair of NIH CSRS Study Section. She was appointed as program co-leader for MCO in 2018. As program co-leader, Dr. Su serves as the site leader for the University of Colorado Boulder Campus and a liaison for the Colorado State University and works closely with MCO co-leader Dr. Ernst to coordinate all aspects of MCO planning, development, execution, and evaluation.