About

Aime T. Franco, Ph.D., is an Associate Professor of Pediatrics specializing in Endocrinology and Diabetes at the University of Pennsylvania. He is a member of the Abramson Cancer Center and holds affiliate memberships with the Center of Excellence in Environmental Toxicology, the Center for Musculoskeletal Disorders, and the Institute for Immunology at the University of Pennsylvania. His research expertise focuses on thyroid cancer, tumor microenvironment, mouse models of cancer, and transgenic mouse models. Dr. Franco's work involves understanding the molecular and cellular mechanisms underlying cancer progression, particularly in thyroid cancers, and he has contributed to the field through studies on miRNA expression, immune suppression in tumor microenvironments, and the signaling pathways involved in thyroid tumor initiation. His academic background includes a B.S./B.A. from the University of Connecticut, an M.S. in Nutritional Sciences from the same institution, a Ph.D. in Cancer Biology from Vanderbilt University, and an M.S. in Social Policy from the University of Pennsylvania.

Research topics

• Internal medicine
• Biology
• Pathology
• Computational biology
• Oncology
• Molecular biology
• Cancer research
• Medicine
• Genetics

Selected publications

• DNA Methylation-Based Risk Stratification and Classification of Pediatric Thyroid Carcinoma

  Clinical Cancer Research · 2026-02-17

  articleOpen access

  PURPOSE: Accurate assessment of invasiveness in pediatric thyroid carcinomas is essential to prevent unnecessary surgery and avoid surgery-associated complications. DNA methylation, a proven molecular biomarker for cancer classification, holds promise for stratifying thyroid cancer risk. The objectives were to determine the epigenetic hallmarks of pediatric thyroid carcinomas and investigate whether DNA methylome profiling is a feasible approach for preoperative risk stratification of this pediatric disease. EXPERIMENTAL DESIGN: We interrogated genome-wide DNA methylation profiles from two separately processed cohorts of pediatric thyroid carcinoma. The reference cohort included 100 samples, consisting of 87 well-differentiated primary tumors-77 papillary and 10 follicular thyroid carcinomas-and 13 matched lymph node metastases. To predict oncogenic drivers and tumor invasiveness, defined by the presence of nodal metastasis, we trained two classifiers on the reference cohort and then evaluated their performance on a second validation cohort of 84 samples, including 83 primary tumors and one lymph node metastasis. RESULTS: We identified distinct methylation patterns associated with tumor invasiveness and key driver mutations, including BRAF p.V600E, RAS-like mutations, kinase fusions, and DICER1 mutations. The differentially methylated regions reflect inflammatory stress and disrupted thyroid development and function, implicating androgen receptor, Hippo, and AP-1 signaling. Leveraging these epigenetic signatures, we developed and validated two methylation-based classifiers that accurately predict tumor invasiveness and oncogenic mutation subgroups. CONCLUSIONS: In patients with pediatric thyroid carcinoma, DNA methylation assays accurately predict tumor invasiveness and driver mutations. Our findings highlight the clinical value of DNA methylation profiling for risk stratification and classification of pediatric thyroid cancers.

  PublisherOA PDFDOI

• KEAP1 mutations activate the NRF2 pathway to drive cell growth and migration, and attenuate drug response in thyroid cancer

  Frontiers in Oncology · 2026-01-07

  articleOpen accessSenior authorCorresponding

  The KEAP1/NRF2 pathway, a major regulator of the cellular oxidative stress response, is frequently activated in human cancers. Often mediated by loss-of-function mutations in KEAP1 , this activation causes increased NRF2 transcriptional activity and constitutive activation of the antioxidant response. While KEAP1 mutations have been well documented in various cancers, their presence and role in thyroid carcinoma have remained largely unexplored. In this study, we sequenced pediatric thyroid tumors and analyzed publicly available datasets, identifying 81 KEAP1 mutations in tumors across a range of histologies. In these tumors, we further identified frequent biallelic loss of KEAP1 via 19p13.2 loss of heterozygosity (LOH). MAPK-activating alterations were found in a subset of KEAP1 -mutant cases, but they were mutually exclusive with 19p13.2 LOH. Transcriptome analysis also revealed significant activation of the NRF2 pathway in KEAP1- mutant tumors. Four additional cases with similar transcriptional profiles but lacking mutational data were identified, likely representing putative KEAP1 mutants. Using in vitro cell line models, we then profiled the functional consequences of KEAP1 knockout in cells with and without known driver alterations. In these models, we show that KEAP1 loss leads to an NRF2-dependent upregulation of AKR1C3 , GCLC , NQO1 , and TXNRD1 , along with increased proliferation and migration irrespective of MAPK mutational status. We also demonstrate that loss of KEAP1 reduces sensitivity of RET fusion-positive cells to selpercatinib, consistent with previous reports that these alterations promote drug resistance in other malignancies. In this study, we comprehensively profile KEAP1 mutations in thyroid tumors, showing that they are more prevalent and functionally significant than previously recognized. These findings position KEAP1 mutations as novel oncogenic variants in thyroid cancer and support the integration of KEAP1/NRF2 pathway profiling into future studies and clinical frameworks.

  PublisherDOI

• Abstract LB-A008: Reversing immune checkpoint inhibitor resistance rherapy in advanced thyroid cancer

  Cancer Immunology Research · 2026-03-05

  article

  Abstract Background: Patients with advanced thyroid cancer have few treatment options and poor survival [e.g. 10% at 10 years for radioactive iodine-refractory differentiated thyroid cancer (DTC)] and immune checkpoint inhibitors (ICI) have not shown benefit in these patients. The goal of this project is to identify novel strategies to improve the efficacy of ICI therapy in thyroid cancer. Prior work showed that suppressive myeloid cells are important contributors to immune escape and ICI resistance in thyroid cancer. In addition, clinical studies have shown that the presence of MDSCs in the peripheral blood of thyroid cancer patients correlates with more advanced disease and recurrence. In melanoma, colon, and lung tumor models, the TLR9 agonist CpG can act on myeloid cells to reduce suppressive function, increase antigen presentation and augment T cell proliferation, activation, and ingress into the tumor. We hypothesized that combined ICI therapy with TLR9 agonist CpG reverse of MDSC suppression to improve anti-tumor efficacy of ICI in DTC. Methods: Mice bearing poorly differentiated BRAFV600E+ papillary thyroid cancer tumors were randomized to treatment with isotype control or ICI (anti-PD1 or anti-PDL1; 250mg/dose i.p., 2x weekly) antibodies, with or without CpG-1826 peritumorally. In addition, we tested ICI with directly conjugated CpG given intraperitoneally compared to ICI alone as a potential systemic therapy. Immune populations in tumor and spleen were evaluated using immunofluorescence, flow cytometry, and in vitro functional assays. Tumor volume was measured thrice weekly. Results: ICI treatment alone (anti-PD1 or anti-PDL1) had no effect on tumor growth compared to isotype control. There were no differences in CD44+ IFNγ+CD8+ effector T cells and CD11b+Gr1hi MDSCs in tumor-bearing mice. Interestingly, peritumoral injection of CpG with concurrent ICI treatment resulted in significantly slower tumor growth (p<0.05) and increased tumor-infiltrating cytotoxic IFNγ+CD8+ T cells. Ex vivo assessment of tumor-associated immune cells showed that CpG treatment abrogated MDSC-mediated suppression of CD8+ T cell proliferation and IFNg production. CpG showed modest but not significant direct effects on CD8+ T cells. Furthermore, PD1+CD8+ T cells and PDL1+ MDSCs were enriched in the TME and wondered whether this checkpoint protein enrichment could be leveraged for targeting of CpG therapy to the tumor. Systemic delivery of CpG is limited by systemic toxicity, whereas intratumoral CpG delivery has limited use for metastatic disease and short intratumoral half-life. allowing for it to be specific targets for Cpg conjugates to deliver directly to the TME. ICI-conjugated CpG (anti-PD1 or anti-PDL1) administered effectively reduced tumor growth and increased population of cytotoxic effector CD44+ IFNγ+ CD8+ T cells in the TME (p<0.05 for anti-PDL1-CpG, trend for anti-PD1-CpG). Conclusion: Our study underscores the role of MDSCs in ICI-resistance seen in advanced thyroid cancer and suggests that TLR9 agonists may improve clinical outcomes for patients. Citation Format: Joah E. Lee, Jaden Nguyen, Jarod Olay, Kyleigh Kimbrell, Amber Lu, Aime T. Franco, Alan L. Epstein, Trevor E. Angell, Melissa G. Lechner. Reversing immune checkpoint inhibitor resistance rherapy in advanced thyroid cancer [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-A008.

  PublisherDOI

• Afirma genomic sequencing classifier performance in young patients with cytologically indeterminate thyroid nodules

  The Journal of Clinical Endocrinology & Metabolism · 2026-02-11 · 1 citations

  articleOpen access

  CONTEXT: The Afirma Genomic Sequencing Classifier (GSC) is validated in patients > 21 yrs. with a 96% negative predictive value (NPV) for malignancy when GSC-(B)enign. Afirma GSC has not been formally studied in patients <21 yrs. with indeterminate thyroid nodules (ITNs). OBJECTIVE: To evaluate Afirma GSC in young patients with ITNs. DESIGN: Retrospective analysis of Afirma GSC testing. SETTING: ITNs referred for molecular testing in a real-world setting. PARTICIPANTS: Forty-nine ITNs from 49 patients < 21 yrs. who had histopathology or two years' clinical follow-up data ascertained. INTERVENTION: none. MAIN OUTCOME MEASURE: Afirma GSC test performance. RESULTS: In 49 ITNs from patients ages 9-20 yrs. (median 18.5 [IQR 17.3-19.8]), 30 were GSC-B and 19 GSC-(S)uspicious, among which 14 (73.7%) were malignant (i.e., true positive, TP) and five (26.3%) were benign (i.e., false positive, FP). All 30 Afirma GSC-B cases were either histologically (n=9) or clinically benign (n=21) (i.e., true negative, TN). All 14 malignancies were GSC-S (sensitivity 100% [95% CI 77-100%]); 30/35 clinically or histologically benign cases were GSC-B (specificity 86% [95% CI 70-95%]). NPV for an Afirma GSC-B result was 100% [95% CI 88-100%]. Genomic alterations were not detected in the 30 GSC-B samples. Among the 14 malignant samples, there were 9 papillary thyroid carcinomas; 1 oncocytic carcinoma; 1 non-invasive follicular thyroid neoplasm with papillary-like nuclear features; and 3 follicular thyroid carcinomas. CONCLUSION: In young patients with ITN, the Afirma GSC demonstrated an excellent negative predictive value when defining a TN result by histology or clinical follow-up.

  PublisherDOI

• Single-cell analysis reveals the cellular and transcriptional heterogeneity of the normal pediatric thyroid

  Frontiers in Endocrinology · 2026-01-29 · 1 citations

  articleOpen accessSenior authorCorresponding

  To enhance the understanding of cellular heterogeneity within the pediatric thyroid, single-nuclei RNA sequencing was used to recover 38,069 non-pathogenic cells from thyroid tissue of three female pediatric/young adult patients. The recovered cells were analyzed using the SWANS (Single Entity Workflow ANalysiS pipeline (version 1.0). Analysis revealed seven major cell types: thyrocytes, endothelial cells, fibroblasts, C cells, T cells, B cells, and myeloid cells. Thyrocytes were the most prominent and heterogeneous cell type. Initially, two dominant thyrocyte subsets were identified based on transcriptional activity, which were subsequently subdivided into seven subclusters. Differentially expressed genes within each cluster support distinct cellular functions, including a metabolically active subset which may be involved in hormone synthesis and a subset involved in the transport of thyroid hormone into circulation. We identified an immune subpopulation originating predominantly from a single sample that was histologically and morphologically similar to the other two samples. This supports that transcriptional changes can be detected and used to identify populations of cells, even in the absence of histologically observable changes. This characterization represents the first comprehensive portraiture of pediatric thyroid gland cells and the first description of normal patient thyrocyte and stromal cell heterogeneity in the absence of adjacent malignancy.

  PublisherOA PDFDOI

• Macrophage abundance in oncocytic thyroid cancer is associated with PD-L1 expression

  Endocrine Oncology · 2025-01-01

  articleOpen accessSenior author

  Objective Oncocytic thyroid cancer (OTC) accounts for 3–5% of thyroid cancers. Previously classified as a subtype of follicular thyroid cancer (FTC), OTC has been redefined by the World Health Organization due to its distinct histopathological and molecular features. OTC demonstrates a more aggressive clinical course than other differentiated thyroid cancers, with higher rates of distant metastases and is often refractory to radioactive iodine therapy (RAI). This study investigates the transcriptional profiles and immune populations of OTC and FTC to identify key differences in gene signatures and immune cell populations. Methods We conducted a comparative analysis of the transcriptional profiles of OTC ( n = 12), FTC ( n = 8), and non-neoplastic thyroid tissues ( n = 9) using targeted RNA sequencing and assessed immune composition through multiplexed immunohistochemistry. PD-L1 and CD68 were evaluated by immunostaining consecutive sections. Results Functional enrichment analysis of differentially expressed genes between OTC and non-neoplastic thyroids revealed upregulation of metabolic pathway genes and downregulation of genes from the cytokine–cytokine receptor pathway. Compared to FTC, OTC cases have decreased expression of thyroid differentiation genes. CD274 /PD-L1 was among the top upregulated genes in OTC vs FTC. PD-L1 protein expression in OTC was tumor cell–derived and correlated with CD68+ macrophage presence, particularly in widely invasive cases. Conclusions The heightened metabolic activity and reduced differentiation of OTC revealed by our transcriptional studies correlate with clinical features such as FDG-PET avidity and diminished RAI response. Marked PD-L1 upregulation in widely invasive OTC suggests immune checkpoint inhibition as a potential therapeutic strategy. Larger, independent studies will be critical to validate these findings.

  PublisherDOI

• Molecular Landscape and Therapeutic Strategies in Pediatric Differentiated Thyroid Carcinoma

  Endocrine Reviews · 2025-02-07 · 9 citations

  reviewOpen access

  There has been significant progress in understanding the molecular landscape of pediatric differentiated thyroid carcinoma (DTC) over the past 2 decades. Classification of pediatric DFC into 3 tiers, RAS-like mutant, BRAF mutant, and kinase fusions, accurately reflects an increasing risk for invasive behavior, including regional and distant metastasis. In clinical practice, somatic oncogene testing for nodules with indeterminate cytology per the Bethesda System for Reporting Thyroid Cytopathology provides objective data to optimize surgical planning. In addition, knowledge of the somatic oncogene for widely invasive carcinomas allows for incorporation of oncogene-specific inhibitory therapy both in the adjuvant and neoadjuvant setting. In the present review, we review the risk factors, clinical presentation, and evaluation of pediatric DTC, highlighting the correlation among ultrasound features, cytology, and oncogenic driver of the tumor. We subsequently propose an integrated, multimodal approach that can be used to improve diagnostic accuracy and reliability for preoperative planning as well as identify and discuss which pediatric patients may benefit from systemic oral targeted therapy.

  PublisherOA PDFDOI

• SWANS: A highly configurable analysis pipeline for single-cell and single-nucleus RNA-sequencing data

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-19 · 3 citations

  preprintOpen access

  Abstract Background Single-cell RNA sequencing (scRNA-seq) is a powerful technique that enables the analysis of gene expression at the individual cell level. Bioinformatic tools for scRNA-seq data analysis have many different options throughout the typical scRNA-seq workflow (normalization, integration, annotation, clustering, and visualization), and the choice of method(s) and parameter(s) at each stage can impact results. Results Here, we introduce SWANS (v2.0), a configurable analysis pipeline that, in a single run, can employ multiple analysis methods, resolutions, and modifiable parameters. The resulting clustering arrangements, differential gene expression results, and other quantitative measurements can be dynamically visualized and compared in a Shiny interactive report to assist in choosing a single analysis schema for annotation and downstream analysis. Once a final approach is chosen, SWANS will perform differential gene expression (DGE) analysis based on experimental conditions and gene set enrichment analysis (GSEA) in addition to creating reports that display figures and interactive tables, quality control metrics, and benchmarking information. SWANS uses Snakemake as a workflow manager, Cell Ranger for alignment and gene expression quantification, Seurat for single cell data analysis, and additional single cell R packages for quality control and downstream single cell analysis. Conclusion SWANS is a tailorable pipeline that provides options for quality control, dimensionality reduction, clustering, differential gene expression analysis, gene set enrichment analysis, and trajectory analysis. Additionally, SWANS generates a series of reports that facilitate sharing large volumes of complex data in a clear and concise manner with other investigators.

  PublisherOA PDFDOI

• What Is the Impact of Glyphosate on the Thyroid? An Updated Review

  Biomedicines · 2025-09-30

  reviewOpen access

  Background/Objectives: Thyroid dysfunction (hypo- and hyperthyroidism) and cancer incidence have increased over the past decades, possibly linked to environmental contributions from endocrine disrupting chemicals (EDCs). Glyphosate is one of the most widely used herbicides globally and has endocrine-disruptive properties. Because of the sensitivity of the thyroid gland to endocrine disruption and the increased glyphosate exposure worldwide, this comprehensive review aimed to summarize studies investigating the link between glyphosate/glyphosate-based herbicides (GBHs) and thyroid dysfunction in human, animal, and in vitro studies. Methods: PubMed, Scopus, and Embase were used to search for original studies assessing glyphosate or GBH exposure and thyroid-related outcomes through December 2024. Data were extracted on study design, population or model, exposure, and thyroid outcomes. A total of 28 studies, including 9 human, 3 in vitro, and 16 animal studies were included. Results: Human studies showed mixed findings with some suggesting associations between glyphosate exposure and altered thyroid hormone levels, while others found no significant effects. Animal studies, particularly in rodents and amphibians, showed thyroid hormone disruption and altered gene expression, especially after perinatal or developmental exposure. In vitro studies reported changes in thyroid-related gene transcription and cell viability, however at concentrations exceeding those seen in humans. Conclusions: While there is some evidence that glyphosate may disrupt thyroid function, differences in study populations, exposure assessment methods, species models, and exposure doses complicated the comparison and summarization of the results. Further mechanistic and longitudinal studies are needed to clarify the thyroid-specific risks of glyphosate exposure.

  PublisherOA PDFDOI

• Single-cell analysis reveals the cellular and transcriptional diversity of thyrocytes in the normal pediatric thyroid

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-17

  preprintSenior authorCorresponding

  ABSTRACT To enhance the understanding of cellular heterogeneity within the pediatric thyroid, single-nuclei RNA sequencing was used to recover 38,069 non-pathogenic cells from thyroid tissue of three pediatric patients. The recovered cells were analyzed using the SWANS ( S ingle Entity W orkflow AN alysi S) pipeline (version 1.0). Analysis revealed seven major cell types: thyrocytes, endothelial cells, fibroblasts, C cells, T cells, B cells, and myeloid cells. Thyrocytes were the most prominent and heterogeneous cell type. Initially, two dominant thyrocyte subsets were identified based on transcriptional activity, which were subsequently subdivided into seven subclusters. Differentially expressed genes within each cluster support distinct cellular functions, including a metabolically active subset which may be involved in hormone synthesis and a subset involved in the transport of thyroid hormone into circulation. We identified an immune subpopulation originating predominantly from a single sample that was histologically and morphologically similar to the other two samples. This supports that transcriptional changes can be detected and used to identify populations of cells, even in the absence of histologically observable changes. This characterization represents the first comprehensive portraiture of pediatric thyroid gland cells and the first description of normal patient thyrocyte and stromal cell heterogeneity in the absence of adjacent malignancy.

  PublisherDOI

Recent grants

• NIH Grant F32CA136178

  NIH · $98k · 2012

• MAPK pathway modulation in thyroid tumorigenesis

  NIH · $2.7M · 2018–2025

Frequent coauthors

• Andrew J. Bauer

  Children's Hospital of Philadelphia

  42 shared

• Richard M. Peek

  33 shared

• Julio C. Ricarte‐Filho

  Children's Hospital of Philadelphia

  30 shared

• Amber Isaza

  Children's Hospital of Philadelphia

  28 shared

• Zubair Baloch

  Philadelphia University

  21 shared

• Nicole Massoll

  University of Arkansas for Medical Sciences

  21 shared

• Ken Kazahaya

  University of Pennsylvania

  21 shared

• Uma Krishna

  20 shared

Education

• Other, Sports Medicine and Athletic Training; Biology

  University of Connecticut

  2000

• M.S., Nutritional Sciences

  University of Connecticut

  2002

• Ph.D., Cancer Biology

  Vanderbilt University

  2007

• M.S., Social Policy

  University of Pennsylvania

  2023