Colorectal and Gastric Cancers

Current Projects
Todd A. Aguilera, MD, PhD

There is a critical need for new therapeutic approaches to treat advanced stage rectal cancer, which has increased incidence in younger people and poor prognosis. Working with a multidisciplinary team, Dr. Aguilera is leading a randomized clinical trial that combines an anti-CD40 agonist immunotherapy with radiation and chemotherapy for locally advanced rectal cancer. The drug aims to activate the protein CD40 on dendritic cells which plays a critical role in generating T-cell immunity. As part of the study, Dr. Aguilera is investigating the factors that influence a patient's immune response to this combination treatment with the goal of optimizing therapy for difficult gastrointestinal cancers. If the proposed treatment is successful, it could become a new therapeutic standard that lowers the risk of metastasis, improves survival, shortens the treatment course and potentially avoids the need for surgery.

Project title: "Immunologic responses to short course radiotherapy in rectal adenocarcinoma and the impact of CD40 agonist immunotherapy"
Institution: University of Texas Southwestern Medical Center
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Robert D. Timmerman, MD
Cancer Type: Colorectal
Research Area: Tumor Immunology
Ben F. Brian, PhD

Abnormal interactions between our immune system and our gut microbes can lead to inflammation that drives colon and gastric cancer growth. Dr. Brian [HHMI Fellow] is investigating how the immune system recognizes and responds to these microbes, and how these interactions contribute to abnormal inflammation that can fuel cancer growth. Microbiota-immune interactions have been generally studied in the context of "clean" laboratory mice, but these models do not fully capture human immunology and the complex interplay between host cells and foreign microbes. To overcome this, Dr. Brian plans to study these interactions in "dirty" mice, colonized by a diverse community of microbes as well as pathogens. He will then use laboratory mice with more defined microbial communities to test how recognition of specific microbes by the immune system is regulated and how disruptions to this regulation contributes to inflammation. Dr. Brian received his PhD from the University of Minnesota, Twin Cities and his BS from the University of California, Santa Barbara.


Project title: "Mechanisms and consequences of microbiota-directed immune responses"
Institution: University of California, Berkeley
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Gregory M. Barton, PhD
Cancer Type: Gastric, Other Cancer, Colorectal
Research Area: Basic Immunology
Fangtao Chi, PhD

Dietary interventions such as caloric restriction (CR) and ketogenic diet (KD) are reported to limit tumor growth partially by modulating stem cell function. The intestine functions as the main organ of nutrient absorption and, due to rapid tissue renewal via intestinal stem cells (ISCs), is sensitive to shifts in the body’s metabolic state before and after eating. Both CR and KD conditions dramatically enhance the activity of an enzyme in ISCs known as HMGCS2. This enzyme controls ketogenesis, the conversion of fatty acids into ketone bodies as a means of producing energy when glucose is unavailable. Dr. Chi aims to dissect the role of ketone body metabolites in modulating intestinal stem cell function and tumor growth. With a better understanding of how intestinal stem cells adapt to diverse diets, he hopes to identify new strategies or dietary interventions that prevent and reduce the growth of cancers in the intestinal tract. Dr. Chi received his PhD from the University of California, Los Angeles and his BS from Zhejiang University.

Project title: "Understanding how ketone body metabolites influence intestinal stemness, immune responses and tumorigenesis"
Institution: Massachusetts Institute of Technology
Award Program: Fellow
Sponsor(s) / Mentor(s): Ömer H. Yilmaz, MD, PhD
Cancer Type: Colorectal
Research Area: Stem Cell Biology
Tin Yi Chu, PhD

Cancer cells form complex interactions with the various normal cells in their environment, including immune cells, fibroblasts, and blood vessels. These interactions are essential for cancer cells to grow, evade immune surveillance, and become metastatic or resistant to certain therapies.  Spatial transcriptomics refers to a method of visualizing the distribution of RNA molecules in a tissue sample, allowing us to assign specific cell types to their locations. Dr. Chu [William Raveis Charitable Fund Quantitative Biology Fellow] aims to develop a statistical framework to infer how different cell types interact with each other based on spatial transcriptomics data. He will use this statistical framework to study cell-cell interactions in both colorectal cancer and inflammatory bowel disease, a risk factor for colorectal cancer.

Dr. Chu will develop a hierarchical Bayesian statistical model to deconvolve the spatial transcriptomic data and then resolve cell type-specific information. Based on the deconvolved spatial data, he will then deploy a Bayesian spatial model to infer the interaction between various cell types.

Project title: "Statistical modeling of cell-cell interactions in normal intestine, inflammatory bowel disease and colorectal cancer using single cell and spatial transcriptomics"
Institution: Memorial Sloan Kettering Cancer Center / The Rockefeller University
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Dana Pe’er, PhD, and Elaine V. Fuchs, PhD
Cancer Type: Colorectal, All Cancers
Research Area: Quantitative Biology
Lauren E. Cote, PhD

Dr. Cote is exploring embryonic development to better understand how cells cooperate and build complex tissues. Since cancer cells often erroneously redeploy developmental programs and behaviors, her research into how neighboring cells align will yield insights into how cancerous cells metastasize and invade other tissues. Dr. Cote is combining tissue-specific genetic manipulations and laser cell ablations with live imaging during Caenorhabditis elegans digestive tract development to reveal how intracellular organization in one cell type can influence the alignment, polarity, and function of cells in the neighboring tissues.

Project title: "Constructing one continuous digestive tract, cell by cell"
Institution: Stanford University
Award Program: Fellow
Sponsor(s) / Mentor(s): Jessica L. Feldman, PhD
Cancer Type: Gastric, Other Cancer, Breast, Colorectal, All Cancers
Research Area: Developmental Biology
Anders B. Dohlman, PhD

In many cancer types, microbiota have emerged as an influential component of the tumor environment. Dr. Dohlman [Meghan E. Raveis Fellow] studies Fusobacterium nucleatum, a bacterial species that colonizes around half of colorectal tumors. The reasons for F. nucleatum’s preferential colonization of these tissues are poorly understood, and investigating this phenomenon could lead to improvements in cancer diagnosis and treatment. To this end, Dr. Dohlman is using computational methods to study strains of cancer-associated F. nucleatum, searching for genomic features that promote colonization of colorectal cancers. In parallel, he is analyzing the genomes of colorectal tumors to identify genetic changes that in turn promote F. nucleatum colonization. Dr. Dohlman received his PhD from Duke University, Durham and his BA from Wesleyan University, Middletown.

Project title: "Identifying the genomic basis for Fusobacterium nucleatum’s colonization of colorectal cancers"
Institution: Dana-Farber Cancer Institute
Named Award: Meghan E. Raveis Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Matthew L. Meyerson, MD, PhD
Cancer Type: Colorectal
Research Area: Microbiology
Xin Gu, PhD

Regulation of gene transcription is a major mechanism cells use to modify the levels of certain proteins in response to their environment. A specific class of genes called immediate-early genes (IEGs) responds rapidly to external stimuli to adjust downstream gene transcription programs before any new proteins are synthesized. Abnormal expression of IEGs has been implicated in multiple types of cancers, as well as in neurological syndromes like addiction. Despite extensive study, the regulation of IEGs remains poorly understood. Dr. Gu’s work focuses on revealing the molecular mechanisms of IEG expression in cells and establishing model systems to study the physiological and disease-related outcomes caused by misregulation of this process. Dr. Gu [National Mah Jongg League Fellow] received her PhD from MIT and her BSc from Peking University.

Project title: "Characterization of a novel pathway regulating the protein degradation of immediate-early genes"
Institution: Harvard Medical School
Named Award: National Mah Jongg League Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Michael E. Greenberg, PhD
Cancer Type: Gastric, Prostate, Sarcoma, All Cancers
Research Area: Cell Biology
Dennis J. Hsu, MD

DNA stores the information for making all the proteins in an organism. Transfer RNA (tRNA) plays a key role in building the proteins from this blueprint. tRNA molecules recognize specific sequences (three-letter codons) and deliver the corresponding amino acids needed to make a protein. Dr. Hsu recently found that certain starvation conditions can cause some tRNAs to be modulated in colorectal cancer cells. He will study the changes in tRNA levels that occur in response to cellular starvation states. He aims to shed light on how cancer cells adapt to starvation, which potentially can lead to new therapeutic approaches to target metabolic dependencies in cancer.

Project title: "Metabolic determinants of codon usage bias in colorectal cancer"
Institution: University of Pittsburgh
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Jeremy N. Rich, MD
Cancer Type: Colorectal, All Cancers
Research Area: Cancer Genetics
Senén D. Mendoza, PhD

In addition to acute illness, viruses can cause cancers. While our understanding of cellular immunity against viruses that have DNA-based genomes is robust, we know less about how cells protect themselves against RNA-based viruses such as hepatitis C, a leading cause of liver cancer. Because many cellular defenses against viruses are known to be shared between mammals and bacteria, Dr. Mendoza [HHMI Fellow] is looking for new cellular defenses against RNA viruses in bacteria and will investigate how these defenses work. The resulting discovery of anti-viral defenses will broaden our understanding of how cells protect themselves against RNA viruses, which will improve our capacity to support patients' immune systems when infected with cancer-causing RNA viruses. Dr. Mendoza received their PhD from the University of California, San Francisco, and their BS from the University of Miami.

Project title: "Discovery and characterization of bacterial immunity against RNA phages"
Institution: Massachusetts Institute of Technology
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Michael T. Laub, PhD
Cancer Type: Blood, Gastric
Research Area: Virology
Ryan Y. Muller, PhD

Epstein-Barr Virus (EBV) is known to cause several human cancers, including nasopharyngeal cancer, gastric cancer, and B-cell lymphomas. During the early stages of viral infection, EBV induces a state of rapid cell division in host cells that promotes oncogenesis. Dr. Muller [HHMI Fellow] studies specific regions of RNA, known as stable introns, which are expressed at abundant levels during early infection but whose role in the viral lifecycle and during oncogenesis is unknown. Investigating how stable introns influence the host cell's biology may reveal insights into EBV-driven oncogenesis and provide a general understanding of the mechanisms that drive cancer progression. Dr. Muller received his PhD from the University of California, Berkeley and his BS from Arizona State University, Tempe.


Project title: "Excised stable introns of Epstein-Barr virus: functions and mechanisms"
Institution: Whitehead Institute for Biomedical Research
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): David P. Bartel, PhD
Cancer Type: Gastric
Research Area: RNA (RNA processing, miRNA and piRNA mechanisms, enzymatic RNAs, etc.)
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