Sofia Maria Morgadinho Ferreira

All Publications

• Merlin's disappearing act:<i> NF2</i> loss conjures pancreatic cancer survival in the hostile tumor microenvironment JOURNAL OF CLINICAL INVESTIGATION Ferreira, S., Attardi, L. D. 2026; 136 (1)

  View details for DOI 10.1172/JCI194395

  View details for Web of Science ID 001669571000013

• Merlin's disappearing act: NF2 loss conjures pancreatic cancer survival in the hostile tumor microenvironment. The Journal of clinical investigation Ferreira, S., Attardi, L. D. 2026; 136 (1)

  Abstract

  Pancreatic cancer cells "live on the edge," starved of nutrients, compressed by abundant stiff stroma, and deprived of oxygen. In this issue, Xu et al. leveraged human pancreas organoid-based CRISPR screens to identify new driver genes in pancreatic ductal adenocarcinoma (PDAC) development. Neurofibromatosis type 2 (NF2) emerged as the top tumor suppressor, whose loss enhances PDAC malignancy. Inactivation of NF2, which encodes the protein Merlin, promoted growth factor independence and enhanced macropinocytosis upon nutrient deprivation. Thus, NF2 status dictates the adaptability of pancreatic tumors under nutrient limitation, with NF2 inactivation endowing PDACs with the ability to survive the constraints of the harsh tumor microenvironment.

  View details for DOI 10.1172/JCI200909

  View details for PubMedID 41480769

• p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program. Cancer discovery Wang, M., Bieging-Rolett, K. T., Kaiser, A. M., Brady, C. A., Lockhart, J. H., Ferreira, S., Nguyen, K. T., Rajeevan, A., Evans, S. A., Zhao, T., Raj, N., Elkrief, A., Tischfield, S. E., Ladanyi, M., Ozawa, M. G., Bui, N. Q., Chen, C. T., Flores, E. R., Attardi, L. D. 2025

  Abstract

  Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.

  View details for DOI 10.1158/2159-8290.CD-25-0525

  View details for PubMedID 41115251

• Inactivation of <i>CDKN2A</i> <SUP> <i>ARF</i> </SUP> promotes p53-independent remodeling of the PDAC tumor microenvironment Ferreira, S., Flowers, B. M., Choi, W., Farina-Morillas, M., Gatto, A., Bhattacharyya, S., Boross, G., Hassan, G., Mulligan, A. S., Vogel, H., Wood, L. D., Weaver, V. M., Winslow, M. M., Petrov, D., Sherman, M. H., Choi, H., Hayes, D., Aguirre, A. J., Seoane, J. A., Attardi, L. D. AMER ASSOC CANCER RESEARCH. 2025

  View details for DOI 10.1158/1538-7445.PANCREATIC25-A030

  View details for Web of Science ID 001588168500030

• Spatial transcriptomic analysis drives PET imaging of tight junction protein expression in pancreatic cancer theranostics. Nature communications Wang, J., Seo, J. W., Kare, A. J., Schneider, M., Pandrala, M., Tumbale, S. K., Raie, M. N., Engudar, G., Zhang, N., Guo, Y., Zhong, X., Ferreira, S., Wu, B., Attardi, L. D., Pratx, G., Iagaru, A., Brunsing, R. L., Charville, G. W., Park, W. G., Ferrara, K. W. 2024; 15 (1): 10751

  Abstract

  Molecular imaging using positron emission tomography (PET) provides sensitive detection and mapping of molecular targets. While cancer-associated fibroblasts and integrins have been proposed as targets for imaging of pancreatic ductal adenocarcinoma (PDAC), herein, spatial transcriptomics and proteomics of human surgical samples are applied to select PDAC targets. We find that selected cancer cell surface markers are spatially correlated and provide specific cancer localization, whereas the spatial correlation between cancer markers and immune-related or fibroblast markers is low. Claudin-4 expression increases ~16 fold in cancer as compared with normal pancreas, and tight junction localization confers low background for imaging in normal tissue. We develop a peptide-based molecular imaging agent targeted to claudin-4 with accumulation to ~25% injected activity per cubic centimeter (IA/cc) in metastases and ~18% IA/cc in tumors. Our work motivates a data-driven approach to selection of molecular targets.

  View details for DOI 10.1038/s41467-024-54761-6

  View details for PubMedID 39737976

  View details for PubMedCentralID 10236159

• Epigenetic priming targets tumor heterogeneity to shift transcriptomic phenotype of pancreatic ductal adenocarcinoma towards a Vitamin D susceptible state. Cell death & disease He, B., Stoffel, L., He, C. J., Cho, K., Li, A. M., Jiang, H., Flowers, B. M., Nguyen, K. T., Wang, K. W., Zhao, A. Y., Zhou, M. N., Ferreira, S., Attardi, L. D., Ye, J. 2024; 15 (1): 89

  Abstract

  As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2'-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.

  View details for DOI 10.1038/s41419-024-06460-9

  View details for PubMedID 38272889

  View details for PubMedCentralID 5858034

• Multifaceted role for p53 in pancreatic cancer suppression. Proceedings of the National Academy of Sciences of the United States of America Mello, S. S., Flowers, B. M., Mazur, P. K., Lee, J. J., Müller, F., Denny, S. K., Ferreira, S., Hanson, K., Kim, S. K., Greenleaf, W. J., Wood, L. D., Attardi, L. D. 2023; 120 (10): e2211937120

  Abstract

  The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53's critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant-p5353,54-which we previously showed is a more robust PDAC suppressor than wild-type p53, to elucidate how p53 acts at the cellular level to dampen PDAC development. Using both inflammation-induced and KRASG12D-driven PDAC models, we find that p5353,54 both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. Moreover, p5353,54 suppresses KRAS signaling in PanINs and limits effects on the extracellular matrix (ECM) remodeling. While p5353,54 has highlighted these functions, we find that pancreata in wild-type p53 mice similarly show less ADM, as well as reduced PanIN cell proliferation, KRAS signaling, and ECM remodeling relative to Trp53-null mice. We find further that p53 enhances chromatin accessibility at sites controlled by acinar cell identity transcription factors. These findings reveal that p53 acts at multiple stages to suppress PDAC, both by limiting metaplastic transformation of acini and by dampening KRAS signaling in PanINs, thus providing key new understanding of p53 function in PDAC.

  View details for DOI 10.1073/pnas.2211937120

  View details for PubMedID 36848578

• Understanding the Arf-p53 axis in PDAC suppression Attardi, L. D., Flowers, B. M., Hanson, K., Mulligan, A. S., Ferreira, S., Bhattacharyya, S., Vogel, H., Wood, L. D., Sherman, M. AMER ASSOC CANCER RESEARCH. 2022: 33-34

  View details for Web of Science ID 000899825600039

• Characterizing acinar cell and ductal cell derived PDACs in mouse models Ferreira, S., Flowers, B. M., Hanson, K. J., Gatto, A., Bhattacharyya, S., Sherman, M. H., Attardi, L. D. AMER ASSOC CANCER RESEARCH. 2022: 40-41

  View details for Web of Science ID 000899825600048