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 the specification of cell fates; nuclear acceptors of signaling and environmental pathways; fundamental mechanisms of transcriptional regulation; the interplay between transcription and RNA processing; mis-regulation of translation; cancer survival pathways; and identification of cancer biomarkers that result from altered gene expression including cell-free DNA biomarkers.
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.
Neuro-oncology Group: Several MCO members are part of a highly collaborative pediatric brain tumor community that also spans DT and THI. A recent focus of this group has been analyzing the benefits and downsides of radiation therapy as part of brain tumor therapy. Their findings demonstrated improved outcomes with a specialized regimen of craniospinal radiation rather than focal radiation in this new pre-clinical model.
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
MCO Program Activity Highlights
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!
MCO co-leaders continue to infuse catchment-relevant issues into the scientific consciousness of MCO members, with the aim that such issues will guide future research in MCO. The MCO program retreat in Nov 2022 featured talks by COE Assistant Director for Dissemination and Implementation (Jan Lowry), and an MCO member who works with Colorado pediatric brain cancer patients (Green), as well as a brainstorming session led by Nikita Pozdeyev, Director of the Colorado Center for Personalized Medicine Translational Informatics, and MCO Affiliate Member.
In 2022, trainees in MCO labs competed in an open challenge with a cash reward for career development activities. They thought of research ideas where they use basic research in their laboratories to address scientific questions relevant to cancer patients in Colorado, our catchment area. We made three Outside-the-Box awards to one MSTP student and two postdoctoral fellows. The winning ideas were to (1) identify risk alleles for melanoma, (2) explore histone modifications in colon cancer, and (3) develop new prostate cancer cell lines, all focusing on African-American patient populations. The last idea is extremely relevant in our catchment, as cell line models from this demographic are nonexistent and prostate cancer is one of two cancers (the other being lung cancer) for which African Americans in Colorado show a higher mortality rate compared to the US average.
In 2023, MCO joined forces with the Office of Community Outreach and Engagement to award three pilot grants for which catchment-relevance was a scorable criterion. Pilots were awarded to Dahl for a project overcoming radiation-induced glioma in Colorado-based children; to a collaborative team of Amaya and colleagues for the role of inflammation in a VA population prone to myelodysplastic syndrome/T-cell leukemia; and to Su for a project that resulted from her outreach efforts in rural Colorado. Based on her visit to rural Colorado communities in 2022, Su initiated a collaboration with a CSU Pueblo professor Jim Carsella to study the effect of heavy metal runoff from mining on genome stability in Drosophila and human cancer models. Dr. Carsella is a chemist and environmental toxicologist who has been studying mining waste in urban settings. The new project is of catchment-relevance because heavy metal concentrations and combinations being tested are designed to match what is found in the rural Pueblo area. These experiments will be complemented by direct testing of soil samples from a mining waste site in Pueblo that have been collected by Dr. Carsella. The project also addresses health disparities because Dr. Carsella has published that lead concentrations in the soil correlate with percentage Hispanics in the population.
We are excited about the annual MCO program retreat which was held Nov 3, 2023. For the first time, it was held jointly with CPC (Cancer Prevention and Control), starting with a 1-hr joint opening session, a shared poster session/lunch break, and final discussion and Happy Hour that lingered into the evening.
The joint opening session introduced the mission of the CPC and MCO members to each other and featured a presentation from COE. We started with lightning talks by select members whose research projects featured catchment connections prominently, to set an example to all. MCO member Ghosh who is collaborating with CPC members (Miller, Keith, and Merrick) to study environmental and molecular risk factors for lung cancer progression was one of the speakers. We then separated to program-specific events. Morning sessions featured new MM speakers to introduce their research interests and goals for collaboration to the whole program.
The lunch break provided opportunities to connect with COE and CPC members and view specific projects on posters, often presented by trainees. Afternoon presentations included MCO Affiliate Member Pozdeyev, Director of the Colorado Center for Personalized Medicine Translational Informatics, who reported on the results of a recently completed pilot-funded project to mine the Colorado Biobank for cancer-specific information. We ended with a panel discussion, moderated by MCO co-leader Su, on how to initiate, maintain, and fund collaborations. Panelists were current MCO members Arnoult, Ramachandran, and Mukherjee who have active collaborations with members of MCO or other programs. We plan to follow up with a pilot award program in which the collaborative nature of the project will be a scorable criterion, so watch for that announcement!
We are also excited to announce a new supergroup started grass-roots-style by early career MCO members Amaya and Caino. It is called “Mito Supergroup” and features Cancer Center and other faculty who focus on mitochondria as 1) signaling hubs in cancer, 2) underlying metabolic vulnerabilities in cancer, and 3) coordinators of cell death in cancer. Please contact Amaya or Caino for more information!
On November 4th, we held our 2024 Program Retreat. Featured were NCI Program officers describing some lesser-known funding initiatives and strategies. The materials from these program officers are available below:
Anu Sharman, Ph.D. - Overview of Funding Opportunities in Cancer Biology
John Giraldes, MS - NCI Drug Development Resources: Stepping Stones, NExT and Consultation Service
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-24-277.html (R01 Clinical Trial Not Allowed)
https://grants.nih.gov/grants/guide/pa-files/PAR-24-291.html (R21 Clinical Trial Not Allowed)
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)
https://grants.nih.gov/grants/guide/pa-files/PAR-22-114.html (RO1)*
* This Collaborative is a two-year administrative supplement, with a total cost of up to $510K over 24 months to support the expansion of CHD research and generate data for new CHD-focused proposals for mechanisms such as the R01.
Division of Cancer Biology
PAR-22-099 - Cancer Tissue Engineering Collaborative: Enabling Biomimetic Tissue-Engineered Technologies for Cancer Research (R01 Clinical Trial Optional)
PAR-23-281 : Research Projects to Enhance Applicability of Mammalian Models for Translational Research (R01 Clinical Trial Not Allowed)
PAR-22-147: Research Projects in Physical Sciences-Oncology (U01 Clinical Trial Optional)
Center for Strategic Scientific Initiatives
Innovative Molecular Analysis Technologies - The IMAT program supports the early-stage development, maturation, and dissemination of novel technologies offering new or improved capabilities for basic, clinical, or epidemiological cancer research.
Informatics Technology for Cancer Research – The ITCR supports the development of critical tools and resources to improve the acquisition, analysis, visualization, and interpretation of data across the cancer research continuum.
Human Cancer Models Initiative
The goal of HCMI is to create up to 1,000 patient-derived next-generation cancer models (i.e., organoids, conditionally reprogrammed cells, neurospheres, or optimal growth condition models) as a community resource.
Patient-Derived Models Repository
The NCI is developing a national repository of Patient-Derived Models (PDMs) comprised of patient-derived xenografts (PDXs), in vitro patient-derived tumor cell cultures (PDCs) and cancer associated fibroblasts (CAFs) as well as patient-derived organoids (PDOs). These models will serve as a resource for public-private partnerships and for academic drug discovery efforts.
NCI Mouse Repository
The NCI Mouse Repository is a resource for murine cancer models, associated strains and mouse embryonic stem cells (mESCs) harboring inducible microRNA species. Managed by the Frederick National Laboratory, mouse strains are free, investigators only have to pay shipping costs.
Oncology Models Forum Webinar Series
This program is devoted to ensuring mammalian models used for translational research questions are appropriate robust representations for those purposes and the models provide reliable and informative data for patient benefit. Contact Christine.Nadeau@nih.gov if interested in attending an upcoming Webinar (December 5, 2:00-3:30 PM ET : OMF and TEC Organoid Models)
Molecular and Cellular Oncology Leadership
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Patricia Ernst, PhD
Program Co-Leader
Dr. Ernst is the Co-Leader for the 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. Dr. Ernst served as Associate Director of the University of Colorado MSTP for seven years and is a former President of the International Society for Experimental Hematology. She serves on the 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.