Chris Roberts

Program: Cancer Biology

Current advisor: Rui Tang, PhD

Undergraduate university: Rhodes College, 2022

Enrollment year: 2023

Research summary
How does loss of the epigenetic regulator CREB-binding protein (CREBBP), mutated in approximately 15% of SCLC patients, drive liver metastasis by altering tumor epigenetic programs and modulating anti-tumor T-cell responses

Small Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a five-year survival rate below 7%. Approximately 70% of patients present with extensive-stage disease, with metastatic dissemination preferentially to the liver. While loss of TP53 and RB1 drives SCLC initiation, the signaling pathways that control SCLC liver organotropic colonization remain poorly defined. Elucidating genetic regulators of these processes in SCLC metastasis will create opportunities to prevent or better treat this lethal disease.
CREB-binding protein (CREBBP) is mutated in approximately 15% of SCLC patients, and its mutation is associated with poor outcomes in many cancer types. As an acetyltransferase, CREBBP controls cell state via regulation of downstream gene expression, mainly through histone modification on H3K27. However, the CREBBP-specific transcriptional programs driving SCLC metastasis remain undefined. As a master epigenetic regulator, CREBBP preserves genomic stability; its dysfunction in human patients increases tumor mutational burden and can trigger immune responses to tumor-derived neoantigens. These results suggest a dual role of CREBBP in tumor-intrinsic progression and immune adaptation in SCLC metastasis. Systematic investigation of CREBBP functions in SCLC-intrinsic signaling and the cancer-immune cross talking will inform novel targeted and combination therapies to better treat or prevent metastatic SCLC.
My training and preliminary work position me uniquely to study CREBBP in SCLC metastasis. My research in Dr. Baker’s lab as an ALSF grant awardee focused on chromatin remodeling in pediatric gliomas established my interest in epigenetic regulation of cancer progression. In Dr. Tang’s lab during PhD training, I developed a high-throughput in vivo platform called Metastasis Originated Barcode Sequencing (MOBA-seq) to systematically identify genetic drivers of SCLC metastasis at single colony resolution (Roberts, Xu, et. al. bioRxiv 2026). Using MOBA-seq, I identified CREBBP as a potent suppressor in SCLC liver metastasis. I also utilized RNA sequencing and spatial transcriptomics to define CREBBP-specific SCLC cell states and tumor microenvironment (TME) alterations in liver metastatic lesions. I hypothesize that CREBBP inactivation rewires the epigenetic landscape in SCLC and remodels the immune TME through regulation of T-Cells to promote SCLC liver metastasis (Figure 1). I will test this hypothesis via the following aims:
AIM 1: Quantitatively dissect CREBBP-specific epigenetic mechanisms in SCLC liver metastasis. Preliminary data showed CREBBP loss significantly enhanced SCLC liver metastasis, whereas loss of its paralog EP300 does not, indicating CREBBP-specific epigenetic targets. To quantitatively dissect CREBBP-specific epigenetic signaling in SCLC liver metastasis, I will first compare CREBBP and EP300 loss in matched SCLC models to define differential effects on SCLC dissemination and colonization. I will also quantify genotype-specific metastatic seeding and clonal expansion to determine how CREBBP loss alters spontaneous SCLC metastasis in GEMMs. Lastly, I will isolate SCLC cells from primary and liver metastatic lesions for single-cell ATAC sequencing and Cut&Run profiling to define CREBBP-specific epigenetic programs driving pro-metastatic cell states. These studies will specify how CREBBP uniquely rewires the epigenome promoting liver metastasis.
AIM 2: Mechanistically define CREBBP-specific T-cell response in metastatic liver immune evasion. Preliminary data indicate altered T-cell infiltration and exhaustion in CREBBP-deficient liver metastases, suggesting CREBBP-specific immune adaptation in SCLC. To uncover mechanisms of CREBBP-deficient immune evasion, I will integrate spatial transcriptomics and single-nucleus RNA-seq to prioritize CREBBP-dependent immune regulators. I will genetically perturb candidate regulators to evaluate their role in shaping metastatic immune fitness in mice with distinct T cell backgrounds. Lastly, I will assess how CREBBP influences response to immune checkpoint blockade. These studies will define how CREBBP signaling dictates cancer–T cell interactions and immune evasion in SCLC liver metastasis.
Significance, impact, and training. This work will identify CREBBP-dependent epigenetic and immune signaling in SCLC liver metastasis. My research will reveal vulnerabilities that may be therapeutically exploited in metastatic disease with CREBBP-mutant patients. The proposed studies provide rigorous training for my PhD in cancer genetics, epigenomics, cancer immunology, mouse modeling, bioinformatics, and biostatistics. Completion of this project will establish my scientific independence and prepare me for a career investigating the genetic and epigenetic mechanisms that govern metastatic cancer evolution.

Graduate publications