Carla Huerta Lopez

All Publications

• Targeting Cell-Matrix Induced Chemoresistance With Regorafenib in a 3D Model of Osteosarcoma. Journal of biomedical materials research. Part A Rao, R. R., Huang, M. S., Zhang, D., Huerta-López, C., Long, C., Rodriguez, G. A., Mozipo, E. A., Sagi, S., Heilshorn, S. C. 2025; 113 (9): e37985

  Abstract

  Over the past four decades, there has been little advancement in treatment strategies for osteosarcoma (OS), the predominant primary bone tumor in the pediatric patient population. Current therapy involves multiple rounds of chemotherapy and surgical resection, which are associated with significant morbidity and suboptimal survival rates. A key challenge in developing new treatments is the difficulty in replicating the OS tumor microenvironment, particularly cell interactions with the extracellular matrix (ECM). This study uses an in vitro model of OS to investigate the cell response to collagen (COL) type I, the primary component of the OS ECM. After 7 days of culture within three-dimensional COL hydrogels, OS cells displayed a more elongated cellular morphology and reduced sensitivity to the standard chemotherapy used for OS treatment compared to cells grown on two-dimensional substrates. To test whether this model could be used to study treatment strategies used for high-risk OS patients, we applied a metronomic regimen combining regorafenib, a multi-tyrosine kinase inhibitor, with front-line chemotherapy to overcome cell-matrix induced chemoresistance. We identified overexpression of the ATP-binding cassette transporter ABCG2, a drug efflux pump, as a potential mechanism of resistance in 3D culture. Regorafenib's inhibitory effect on ABCG2 suggests a mechanistic basis for its ability to restore chemosensitivity in 3D culture. Altogether, these findings highlight the importance of cell-matrix interactions in in vitro OS models, provide valuable insights into a matrix-induced mechanism of OS chemoresistance, and suggest an approach to its treatment.

  View details for DOI 10.1002/jbm.a.37985

  View details for PubMedID 40938276

• Organoid bioprinting to pattern the matrix microenvironment. Current opinion in biomedical engineering Zhang, D., Huerta-López, C., Heilshorn, S. C. 2025; 35

  Abstract

  The development of organoid cultures has propelled the fields of cell biology, tissue engineering, and regenerative medicine forward. These cultures better mimic in vivo tissue structure and function compared to 2D cell culture; however, organoids are limited in size and do not inherently allow precise control over tissue architecture and cell heterogeneity. Hand-wrought organoid biofabrication approaches enable the production of larger and more complex tissues, but they still lack reproducible control of spatiotemporal tissue patterns. In contrast, bioprinting is a collection of machine-wrought technologies that are emerging as powerful tools in tissue engineering and disease modeling, but have not yet been widely applied to organoids. When combined with advances in biomaterials science, bioprinting offers the possibility to control spatiotemporal cellular and microenvironmental features. The interactions between biomaterial inks, support baths, and embedded cells provide the opportunity to guide the maturation and functionality of engineered tissues. This review describes how recent advances in organoid technology, bioprinting, and biomaterials science can be integrated to achieve spatiotemporal patterning of four aspects of the microenvironment: matrix structure and mechanics, matrix ligands and morphogens, co-culture of multiple cell types, and incorporation of vasculature. These insights underscore the potential for organoid bioprinting to advance the fabrication of in vitro tissue mimics for applications in drug screening, disease modeling, and regenerative medicine.

  View details for DOI 10.1016/j.cobme.2025.100607

  View details for PubMedID 40717815

  View details for PubMedCentralID PMC12288624

• Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matrices. Nature communications Huang, M. S., LeSavage, B. L., Ghorbani, S., Gilchrist, A. E., Roth, J. G., Huerta-López, C., Mozipo, E. A., Navarro, R. S., Heilshorn, S. C. 2025; 16 (1): 5213

  Abstract

  Neural progenitor cells (NPCs) hold immense potential as therapeutic candidates for neural regeneration, and materials-based strategies have emerged as attractive options for NPC expansion. However, maintaining NPC stemness has proven challenging in vitro, due to their propensity to form cell-dense neurospheres. While neurospheres promote cell-cell interactions required for NPC stem maintenance, they also restrict oxygen transport, leading to hypoxia and limited cell expansion. To overcome these limitations, we investigate two materials-based approaches to maintain NPC stemness: 1) physical matrix remodeling within a viscoelastic, stress-relaxing hydrogel and 2) matrix-induced N-cadherin-like signaling through a cell-instructive peptide. While viscoelasticity alone is sufficient to maintain NPC stemness compared to an elastic environment, NPCs still preferentially form neurospheres. The addition of N-cadherin-like peptides promotes a distributed culture of NPCs while maintaining their stemness through cadherin-mediated signaling, ultimately exhibiting improved long-term expansion and neural differentiation. Thus, our findings reveal matrix viscoelasticity and engineered N-cadherin-like interactions as having a synergistic effect on NPC expansion and differentiation within 3D matrices.

  View details for DOI 10.1038/s41467-025-60540-8

  View details for PubMedID 40473615

  View details for PubMedCentralID 5682670

• Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids. Nature materials LeSavage, B. L., Zhang, D., Huerta-López, C., Gilchrist, A. E., Krajina, B. A., Karlsson, K., Smith, A. R., Karagyozova, K., Klett, K. C., Huang, M. S., Long, C., Kaber, G., Madl, C. M., Bollyky, P. L., Curtis, C., Kuo, C. J., Heilshorn, S. C. 2024

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) is characterized by its fibrotic and stiff extracellular matrix. However, how the altered cell/extracellular-matrix signalling contributes to the PDAC tumour phenotype has been difficult to dissect. Here we design and engineer matrices that recapitulate the key hallmarks of the PDAC tumour extracellular matrix to address this knowledge gap. We show that patient-derived PDAC organoids from three patients develop resistance to several clinically relevant chemotherapies when cultured within high-stiffness matrices mechanically matched to in vivo tumours. Using genetic barcoding, we find that while matrix-specific clonal selection occurs, cellular heterogeneity is not the main driver of chemoresistance. Instead, matrix-induced chemoresistance occurs within a stiff environment due to the increased expression of drug efflux transporters mediated by CD44 receptor interactions with hyaluronan. Moreover, PDAC chemoresistance is reversible following transfer from high- to low-stiffness matrices, suggesting that targeting the fibrotic extracellular matrix may sensitize chemoresistant tumours. Overall, our findings support the potential of engineered matrices and patient-derived organoids for elucidating extracellular matrix contributions to human disease pathophysiology.

  View details for DOI 10.1038/s41563-024-01908-x

  View details for PubMedID 38965405

  View details for PubMedCentralID 5704175