Research in the Romano Lab focuses on understanding why cancers resist therapy and how durable responses can be achieved by integrating targeted therapies with immune-modulating strategies. We combine genetically engineered and syngeneic mouse models, functional genomics, computational biology, and translational studies to uncover the molecular and cellular mechanisms that drive therapeutic resistance. Although melanoma is our principal model system, the concepts we investigate extend broadly to RAS/MAPK-driven malignancies and other solid tumors. Our research is organized around three interconnected areas.
Tumor-immune interactions in minimal residual disease
Trajectory Analysis on scRNAseq data from intratumoral mouse T cells.
Even the most effective targeted therapies rarely eliminate every tumor cell. A small population of drug-tolerant cells can survive treatment, persist as minimal residual disease (MRD), and eventually seed relapse and metastasis. We investigate how oncogenic signaling reshapes the tumor microenvironment during this vulnerable stage and how immune-stromal interactions influence the survival of residual tumor cells. By defining chemokine networks and other mechanisms of immune regulation, we aim to develop therapeutic strategies that recruit and activate anti-tumor immunity to eradicate MRD and prevent disease recurrence.
Tumor suppressor loss as a driver of therapeutic resistance
Representative tumor bioluminescence imaging of mice with metastatic disease.
Current precision oncology has largely focused on targeting oncogenic drivers such as BRAF and EGFR. However, resistance frequently arises through alterations in tumor suppressor pathways that remain difficult to target directly.
Our laboratory uses genome-scale functional genomics, CRISPR-based approaches, and preclinical models to identify tumor suppressor-mediated resistance mechanisms and the signaling dependencies they create. These studies enable the development of rational combination therapies that anticipate resistance and improve the durability of targeted treatments.
Immunological mechanisms of HIV and cancer co-morbidity
Multiplex immunofluorescence of intratumoral T cells of a melanoma patient.
People living with HIV (PLWH) remain at increased risk of developing several non-AIDS-defining malignancies and often experience poorer outcomes following cancer therapy despite effective antiretroviral treatment. We investigate how chronic HIV-associated immune dysfunction alters the tumor microenvironment, influences therapeutic response, and contributes to resistance. By understanding the interplay between antiviral immunity, tumor immunity, and oncogenic signaling, we seek to develop treatment strategies that improve outcomes for PLWH while uncovering broader principles of immune dysfunction in cancer.
Core Expertise
The Romano Lab integrates experimental and computational approaches to investigate cancer biology across multiple scales, from molecular mechanisms to preclinical therapeutic validation. Our core expertise includes:
- Preclinical cancer models: Genetically engineered mouse models (GEMMs), syngeneic models, patient-derived and cell line xenografts.
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Functional genomics: CRISPR-Cas9, Cre-LoxP, knock-in/knock-out models, and genetic perturbation strategies to identify and validate therapeutic targets.
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Target discovery and therapeutic screening: Genome-wide CRISPR screens, focused genetic screens, and small-molecule screening to uncover actionable vulnerabilities and resistance mechanisms.
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Drug delivery technologies: Development of micro- and nanoparticle-based platforms for targeted delivery of immune-modulating therapeutics.
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Computational and systems biology: Analysis and integration of multi-omic datasets — including bulk and single-cell RNA sequencing, whole-exome sequencing, proteomics, and spatial datasets — from patient specimens and preclinical models.
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Translational science: Multidisciplinary collaborations with academic and clinical partners in the United States and internationally to accelerate the translation of laboratory discoveries into novel therapeutic strategies.
Open Positions
Students (graduate and undergraduate) and potential collaborators are always welcome to contact Dr. Romano for questions, ideas and suggestions!
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