Current & Past Odyssey Fellows

Mehdi Chaib, Ph.D.

Odyssey Fellow (2024-2027)
Department of Immunology
Supported by: CFP Foundation

Red-Pulp-Like Tumor-Associated Macrophages Expressing Vascular Cell Adhesion Molecule 1 Drive Resistance to Immunotherapy

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1), play a pivotal role in unleashing T cell control of tumors. However, their efficacy is hindered by immunosuppressive myeloid cells, particularly tumor-associated macrophages (TAMs) within the tumor microenvironment (TME). Recent technological advancements yielded tools like high-dimensional single-cell analysis, fate-mapping, and spatial transcriptomics which unveiled the intricate biology and heterogeneity of TAMs. Despite these breakthroughs, targeting TAMs in clinical settings remains challenging due to gaps in understanding TAM subset-specific adaptations to environmental cues, guided by lineage-determining and stimulus-responsive transcription factors (TFs). Consequently, understanding the biology, gene programs, and functions of TAM subsets that contribute to ICI resistance is crucial for identifying novel therapeutic targets. Preliminary findings indicate that a distinct subset of TAMs expressing vascular cell adhesion molecule 1 (VCAM-1) is increased by anti-CTLA-4 in both mice and human tumors. VCAM-1+ TAMs led to a dysfunctional activation of CD8 T cells ex vivo and promoted resistance to anti-CTLA-4 in vivo in adoptive transfer experiments. Notably, VCAM-1+ TAMs exhibit a gene signature resembling that of splenic red-pulp macrophages (RPM) which may offer clues as to the origin and function of VCAM-1+ TAMs by understanding RPM biology.

Rareș Drula, Ph.D.

Odyssey Fellow (2024-2027)
Department of Translational Molecular Pathology
Supported by: Theodore N. Law for Scientific Achievement

Extracellular vesicle encapsulated miRNAs as
surrogates and conveyors of oncogenic estrogen signaling in ER+ breast cancer

Estrogen (E2) is a major driver of estrogen receptor-positive (ER+) breast cancer, accounting for over two-thirds of all breast cancer cases worldwide and representing a significant challenge in cancer management due to its role in promoting tumor growth and progression. While E2 is well known for its genomic and non-genomic signaling pathways within tumor cells, its role in shaping the tumor microenvironment (TME) through extracellular vesicles (EVs) has gained attention as a critical mechanism of intercellular communication. EVs, particularly their microRNA (miRNA) cargo, are increasingly recognized for their ability to influence recipient cell behavior, facilitating processes such as immune modulation, stromal reprogramming, and metastasis. E2 has been shown to enhance EV secretion and to regulate the selective enrichment of specific miRNAs, such as the let-7 family, which are associated with metabolic status and clinical characteristics, including menopausal state and body mass index. These miRNA-enriched EVs have been implicated in modulating immune responses, such as altering macrophage activation, potentially promoting immune evasion within the TME. The broader influence of E2-regulated EVs on tumor progression and immune dynamics underscores the importance of defining their miRNA composition and functional roles in ER+ breast cancer. Research into E2-regulated EVs also extends to adipocytes, a key source of extragonadal E2 in the breast stroma, particularly in obesity. Adipocyte-derived E2 and its impact on EV cargo represent an important area of study, given the established link between obesity, E2 levels, and poor breast cancer outcomes. Investigations into the interplay between tumor-derived and adipocyte-derived EVs are expected to clarify how hormonal and metabolic factors converge to influence the TME and tumor progression. Validation of findings in EVs isolated from patient samples is being pursued to establish their clinical relevance, particularly as non-invasive biomarkers for disease progression, therapeutic response, and relapse. In addition to identifying potential diagnostic applications, the study of EV miRNAs aims to uncover their contributions to tumor-promoting paracrine signaling networks. This research addresses critical gaps in understanding the indirect effects of E2 signaling, offering insights into how EVs mediate communication between tumor cells, adipocytes, and immune cells, and highlighting their potential as targets for novel therapeutic interventions in ER+ breast cancer.

Jiexi Li, Ph.D.

Odyssey Fellow (2024-2027)
Department of Cancer Biology
Supported by: Odyssey Expansion Fund

Developing an immuno-oncology therapy to target APC-deficient KRAS-mutant colorectal cancer

Colorectal cancer (CRC) is one of the most lethal cancers worldwide causing over 650,000 deaths each year. In CRC, the signature mutations are loss of function (LOF) of tumor suppressor APC and p53 and KRAS oncogenic mutations (KRAS*). Among all CRC patients, 40% have co-occurrence of APC-LOF and KRAS* (Li, et al., Nature, 2023)1, yet no effective therapies have been developed for this patient population. LOF of APC serves as a critical initiating event in CRC and activates the pro-tumor WNT signaling network (Li, et al., Genes & Dev, 2021)2. Our previous study showed that tryptophan 2,3-dioxygenase 2 (TDO2) is an essential gene for cancer cells with APC deficiency, driving cancer cell glycolysis and immune suppression. In APC-LOF KRAS-wildtype (WT) murine CRC model, knockdown of TDO2 and TDO2 inhibitor (TDO2i) both impaired tumor growth by provoking a dramatic influx of CD8+ T cells into the tumor microenvironment (TME) and significantly reducing the infiltration of immune suppressive macrophages3. However, our pilot study showed that this effectiveness was not observed in CRC with KRAS* alongside APC-LOF. Our lab has revealed that KRAS* (most commonly at G12D) also suppresses CRC immune response partially through recruiting myeloid derived suppressor cells (MDSCs) and decreasing CD8+ T cells infiltration4, which can be reversed by MDSC blockade leading to sensitivity

to anti-PD-1 therapy4. The novel KRAS G12D inhibitor (KRASi) MRTX1133 has exhibited efficacy against pancreatic cancer but showed meager effectiveness in CRC5,6, potentially due to additional immune suppression mechanisms driven by other mutations, such as APC-LOF. However, the effectiveness of co-targeting APC-LOF and KRAS* remains unexplored despite its great promise in advancing therapeutic strategies. Moreover, CRC with APC-LOF and KRAS* is infamously resistant to immune checkpoint inhibitors (ICIs) due to its “immunologically cold” TME. Thus, harnessing the increased CD8+ T cell influx triggered by targeting TDO2 and/or the KRAS-MDSC axis may unlock the efficacy of ICI. One specific immune checkpoint, TIM3, has drawn our interest as it was upregulated in tumors by both TDO2i and genetically shutting down KRAS*, suggesting anti-TIM3 may magnify the benefits of the dual inhibitor treatment. More importantly, ICIs such as anti-TIM3 have demonstrated durable effects due to the memory of the immune system in preclinical studies7. To this end, we hypothesize that TDO2i and KRASi combination will achieve synergistic anti-tumor activities in APC-deficient KRAS-mutant CRC and the addition of anti-TIM3 may further boost the effect and lead to durable survival benefit. Our lab has established two CRC genetically engineered mouse models (GEMMs) containing conditional null APC and p53 alleles with or without doxycycline (dox)-inducible KRASG12D (designated “iKAP” or “iAP”, respectively) which faithfully mimic human CRC development and sex differences (Li, et al., Nature, 2023)1,8.

Chenchu Lin, Ph.D.

Odyssey Fellow (2023-2026)
Department of Bioinformatics and Computational Biology
Supported by: Odyssey Expansion Fund

Genetic modeling of oncology drug response through CRISPR/enCas12a multiplexed perturbation platform

Precision oncology requires accurate mapping of genotype to phenotype to identify and deliver the specific and accurate therapy. Large-scale molecular profiling of tumors and genome-scale CRISPR/Cas9 knockout screens in cancer cell lines have provided revolutionary resources for cancer precision therapy and subsequent targeted drug development. However, CRISPR screens are often poor predictors of drug response, especially for “dirty” agents whose efficacy depends on targeting multiple members of a gene family (e.g. MEK inhibitor trametinib, a treatment for metastatic melanoma, targets both MAP2K1 and MAP2K2). To date, a technology that can be used to accurately model drug response by genetic perturbation is unavailable in human cells. Therefore, we propose to develop a highly multiplexed CRISPR perturbation screening platform to study clinically relevant genetic interactions rapidly and inexpensively. My hypothesis is to engineer the CRISPR/enCas12a system to target multiple genes simultaneously and provide an accurate genetic model of drug response and polypharmacology. My goal is to develop and utilize this polygenic perturbation platform to characterize the functional genomics of the FDA-approved oncology drug targets and discover novel synthetic vulnerabilities in drug-resistant tumors. This work will not only reveal how drug targets correlate with gene dependencies in complex cancer progression but provide a more accurate theoretical basis for cancer therapeutic intervention, and precision medicine. We are eager to employ this platform to develop combinatorial therapy options to benefit drug-resistant cancer patients.

Ryan Mulqueen, Ph.D.

Odyssey Fellow (2024-2027)
Department of Systems Biology
Supported by: Cockrell Foundation Award for Scientific Achievement

Epigenomic response to copy number alterations in early breast cancer

Tetraploidization of the genome, known as whole genome doubling (WGD), may be the most dramatic copy number variation (CNV) event in cancer. WGD occurs in 44% of breast cancer tumors, and ~1/3rd of all tumor types, across cancers. One theory is that WGD confers a “genomic buffer” to explore evolutionary space during progression to aggressive cancer. All major driver mutations of invasive breast cancer, including WGD have been identified in premalignant tissue. Though premalignant carcinoma increases the risk of invasive cancer by 10-fold, only 5% of untreated cases progress within 10 years, therefore, the transition to invasive cancer is reliant on mechanisms beyond mutation. This proposal is set to investigate a mechanism with a currently unknown role ¾ the epigenomic response to gene dosage changes. Our central hypothesis is that WGD/CNV events disrupt the epigenome across cancer-relevant genes and this disruption persists through many cell generations.

Three obstacles have hindered the study of this phenomenon: 1) heterogeneous cell states, due to rapid epigenomic response; 2) diverging lineages, due to high mutation rates after CNVs/WGD; 3) difficulty in capture of initiating CNV/WGD events in patient samples, due to occurring as early driver events.To overcome these difficulties, I will use the support of the Odyssey Fellowship to develop new single cell co-assay technologies to study cell lines models and patient samples. Thousands of single cell profiles from induced WGD in cell culture will generate a nuanced progression of epigenetic responses, addressing the first obstacle. I will measure expression (RNA), genome conformation (Hi-C), chromatin accessibility (ATAC), and methylome (MET) changes, each paired to whole genome sequencing (scWGS) in the same cell, providing lineage information and thus overcoming the second obstacle. Finally, I will develop a scWGS/MET method for formalin-fixed paraffin embedded (FFPE) tissue, allowing capture of early precancerous events, addressing the third. Together these advances will vastly improve our understanding of CNV and WGD events in early breast cancer progression.

Melanie K. Prodhomme, Ph.D.

Odyssey Fellow (2023-2026)
Department of Epigenetics and Molecular Carcinogenesis
Supported by: The Kimberly Clark Foundation

The regulation of DNA polymerase theta by ATM in non-small cell lung cancer

Cancer is characterized by uncontrolled growth and spread of abnormal cells following one or more mutational events. One of the main characteristics of tumor development is the acquisition of genomic instability leading to mutational events. This genomic instability can be partly attributed to inaccurate DNA damage repair. Several repair pathways can be used to repair DNA damage, but a recently discovered pathway, called Theta Mediated End Joining (TMEJ), has been found to have an important role during cancer development, given its strong mutagenic capacity. Overexpression of DNA polymerase theta (Polθ, encoded by the POLQ gene), a key enzyme in the TMEJ pathway, is found in many cancers. However, the function and the regulation of Polθ and TMEJ are still poorly understood. In recent years, TMEJ has been at the center of various studies, given its strong mutagenic ability but also for its synthetic lethality in BRCA1-deficient tumors, where Polθ is essential for their survival. Polθ has therefore become a new therapeutic target in many cancers. But BRCA1 deficient tumors are not the only ones that can benefit from synthetic lethality with Polθ. There are strong indications that ATM has a genetic interaction with Polθ. As Non-Small Cell Lung Cancer (NSCLC) tumors are reported to have epigenetic suppression of ATM (undetectable in ~ 40% of lung adenocarcinomas), this makes them a good model to study the close link between Polθ and ATM. Unfortunately, ATM's role in the regulation of Pol and TMEJ is not yet known.

My overall hypothesis is that ATM has the ability to regulate the level of Polθ protein, and therefore, regulates the TMEJ activity. Based on my preliminary data, ATM appears to affect post-translational degradation of Polθ. Therefore, the dual deletion of Polθ and ATM could result in synthetic lethality in NSCLC. This discovery could be of great help in the treatment of these tumors. In conclusion, this whole project will allow us to better understand the functioning of Polθ and TMEJ in the context of regulation by ATM, especially in lung cancer. Finally, we will be able to determine new biomarkers and signatures to guide patients towards a more appropriate therapy.