Engineering functional 3-dimensional patient-derived endocrine organoids for broad multiplatform applications

Baregamian, Naira; Sekhar, Konjeti R.; Krystofiak, Evan; Vinogradova, Maria; Thomas, Giju; Mannoh, Emmanuel A.; Solórzano, Carmen C.; Kiernan, Colleen M.; Mahadevan‐Jansen, Anita; Abumrad, Naji N.; Freeman, Michael L.; Weiss, Vivian L.; Rathmell, Jeffrey C.; Rathmell, W. Kimryn

doi:10.1016/j.surg.2022.09.027

Cited by 7 publications

(6 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The development of patient-derived 3D organoid models has advanced the field of cancer biology. However, 3D organoid models of endocrine cancers have rarely been reported and their application as a therapeutic model has not yet been realized ( 46 ). In this study, we have established PDO and PDXO from patients with ACC, which until now lacked preclinical models.…”

Section: Discussionmentioning

confidence: 99%

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts

Arakawa,

Jo,

Kumar

et al. 2024

Cancer Research Communications

View full text Add to dashboard Cite

Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme E1 inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response (UPR), and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage adrenocortical carcinoma. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors.

show abstract

Section: Discussionmentioning

confidence: 99%

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts

Arakawa,

Jo,

Kumar

et al. 2024

Cancer Research Communications

View full text Add to dashboard Cite

show abstract

“…Under sterile intraoperative conditions, six parathyroid gland tissues were biopsied ex vivo using an FNA-based technique to establish parathyroid patient-derived organoids in semi-solid culture conditions developed, optimized, and previously described by our group ( 2 , 4 , 5 ). Parathyroid PDOs were grown in complete organoid culture media as previously described by our group ( 2 ) for 7-10 days, imaged using color brightfield microscopy (Cytation5 BioTek, Winooski, VT), then split into two study arms with the first group of parathyroid PDOs (counted 100 parathyroid PDOs per patient) for metabolomic and bioenergetic analyses, and the second group cryopreserved for downstream functional analysis for PTH secretion.…”

Section: Methodsmentioning

confidence: 99%

“…Cryopreserved parathyroid PDOs from all patients were rapidly thawed and immediately resuspended in warmed complete organoid media in a 50 mL conical tube, as previously described by our group ( 2 , 5 ). Parathyroid organoids were then centrifuged at 1200 rpm for 5 min at 22 0 C. Supernatant was carefully removed, and the parathyroid organoid pellet was gently resuspended in warmed complete organoid media and plated in a 24-well ultra-low attachment plate (Corning, #3473).…”

Section: Methodsmentioning

confidence: 99%

“…Parathyroid organoids are a novel platform and are actively being explored for both in vitro and in vivo studies. The Baregamian laboratory has developed a comprehensive organoid program of endocrine patient-derived organoids (PDO) of thyroid, parathyroid, and adrenal neoplasms for translational applications using a fine-needle aspiration (FNA)-based technique ( 2 ), and demonstrated preserved multicellular 3-dimensional (3D) ultrastructure, functionally intact, hormone-secreting endocrine organoids of parathyroid, medullary thyroid, and cortisol-secreting adrenal cancer organoids. Parathyroid PDOs revealed a preserved Calcium-sensing receptor (CaSR) expression, autofluorescence characteristic of parathyroid tissues, and sustained PTH secretion over extended periods of time in 3D in vitro culture.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metabolism of parathyroid organoids

et al. 2023

Self Cite

View full text Add to dashboard Cite

IntroductionWe successfully developed a broad spectrum of patient-derived endocrine organoids (PDO) from benign and malignant neoplasms of thyroid, parathyroid, and adrenal glands. In this study, we employed functionally intact parathyroid PDOs from benign parathyroid tissues to study primary hyperparathyroidism (PHPT), a common endocrine metabolic disease. As proof of concept, we examined the utility of parathyroid PDOs for bioenergetic and metabolic screening and assessed whether parathyroid PDO metabolism recapitulated matched PHPT tissues.MethodsOur study methods included a fine-needle aspiration (FNA)-based technique to establish parathyroid PDOs from human PHPT tissues (n=6) in semi-solid culture conditions for organoid formation, growth, and proliferation. Mass spectrometry metabolomic analysis of PHPT tissues and patient-matched PDOs, and live cell bioenergetic profiling of parathyroid PDOs with extracellular flux analyses, were performed. Functional analysis cryopreserved and re-cultured parathyroid PDOs for parathyroid hormone (PTH) secretion was performed using ELISA hormone assays.Results and discussionOur findings support both the feasibility of parathyroid PDOs for metabolic and bioenergetic profiling and reinforce metabolic recapitulation of PHPT tissues by patient-matched parathyroid PDOs. Cryopreserved parathyroid PDOs exhibited preserved, rapid, and sustained secretory function after thawing. In conclusion, successful utilization of parathyroid PDOs for metabolic profiling further affirms the feasibility of promising endocrine organoid platforms for future metabolic studies and broader multiplatform and translational applications for therapeutic advancements of parathyroid and other endocrine applications.

show abstract

“…Additionally, there is one report of PDOs established from fine-needle biopsies of human tumors. Baregamian et al [ 100 ] reported the successful generation of organoids from ACC and adrenal neoplasm samples in ultra-low attachment (ULA) plates. These organoids were formed in the time range 1–3 weeks and maintained cortisol secretion for only 2–3 passages.…”

Section: Adrenalmentioning

confidence: 99%

Three Dimensional Models of Endocrine Organs and Target Tissues Regulated by the Endocrine System

Luca,

Zitzmann,

Bornstein

et al. 2023

Cancers

View full text Add to dashboard Cite

Immortalized cell lines originating from tumors and cultured in monolayers in vitro display consistent behavior and response, and generate reproducible results across laboratories. However, for certain endpoints, these cell lines behave quite differently from the original solid tumors. Thereby, the homogeneity of immortalized cell lines and two-dimensionality of monolayer cultures deters from the development of new therapies and translatability of results to the more complex situation in vivo. Organoids originating from tissue biopsies and spheroids from cell lines mimic the heterogeneous and multidimensional characteristics of tumor cells in 3D structures in vitro. Thus, they have the advantage of recapitulating the more complex tissue architecture of solid tumors. In this review, we discuss recent efforts in basic and preclinical cancer research to establish methods to generate organoids/spheroids and living biobanks from endocrine tissues and target organs under endocrine control while striving to achieve solutions in personalized medicine.

show abstract

Engineering functional 3-dimensional patient-derived endocrine organoids for broad multiplatform applications

Cited by 7 publications

References 25 publications

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts

Metabolism of parathyroid organoids

Three Dimensional Models of Endocrine Organs and Target Tissues Regulated by the Endocrine System

Contact Info

Product

Resources

About