Daily Endocrinology Research Analysis
Top endocrinology advances today span regenerative and precision medicine: a human adrenocortical organoid platform that secretes cortisol, responds to physiological stimuli, rescues adrenalectomized mice, and models PRKACA-driven Cushing’s; a cell type-resolved proteomic/phosphoproteomic atlas that maps inflammatory signaling across islet alpha, beta, and delta cells; and preclinical evidence that Wee1 inhibition (AZD1775) shows antitumor activity and combinatorial potential in adrenocortical c
Summary
Top endocrinology advances today span regenerative and precision medicine: a human adrenocortical organoid platform that secretes cortisol, responds to physiological stimuli, rescues adrenalectomized mice, and models PRKACA-driven Cushing’s; a cell type-resolved proteomic/phosphoproteomic atlas that maps inflammatory signaling across islet alpha, beta, and delta cells; and preclinical evidence that Wee1 inhibition (AZD1775) shows antitumor activity and combinatorial potential in adrenocortical carcinoma.
Research Themes
- Organoid-based regenerative endocrinology
- Single-cell-resolved proteomics of islet biology
- Targeted DNA-damage checkpoint therapy in adrenal cancer
Selected Articles
1. Human adrenocortical organoids for tissue regeneration and disease modeling.
The authors establish expandable human adrenocortical organoids that preserve zona fasciculata identity, secrete cortisol, and respond to physiological stimuli. These organoids rescued adrenalectomized mice and modeled PRKACA L206R–driven cortisol-producing adenomas, creating a robust platform for adrenal disease modeling and regenerative applications.
Impact: First demonstration of human adrenocortical organoids with functional steroidogenesis, in vivo rescue, and precise genetic disease modeling addresses a major unmet need in adrenal insufficiency and Cushing’s research.
Clinical Implications: Provides a translational platform for autologous/regenerative approaches to primary adrenal insufficiency and for preclinical drug testing in cortisol-producing tumors driven by PRKACA mutations.
Key Findings
- Established expandable human adrenocortical organoids preserving zona fasciculata identity and cortisol secretion.
- Organoids responded to physiological stimuli and rescued adrenalectomized mice.
- Introduced PRKACA L206R to model cortisol-producing adenomas for Cushing’s syndrome research.
Methodological Strengths
- Human-derived organoids with functional readouts (hormone secretion and in vivo rescue).
- Genetic engineering (PRKACA L206R) enabling precise disease modeling.
Limitations
- Organoid lineage predominantly reflects zona fasciculata; zona glomerulosa/reticularis functions were not detailed.
- Long-term safety, immunogenicity, and scalability for transplantation were not evaluated.
Future Directions: Define protocols to generate multi-zonal adrenal organoids, assess engraftment durability and immune compatibility, and deploy the platform for drug screening in adrenal tumors and steroidogenesis disorders.
2. Decoding adult murine pancreatic islet cell diversity through cell type-resolved proteomics and phosphoproteomics.
Using cell sorting and sensitive mass spectrometry, the study delivers the first deep proteomic and phosphoproteomic atlas of adult murine islet alpha, beta, and delta cells. IFN-γ triggered inflammatory signatures across all endocrine cell types, and >7000 phosphosites per cell type revealed cell-specific signaling networks.
Impact: Creates a foundational protein- and phosphorylation-level reference for islet biology and autoimmunity, enabling hypothesis-driven target discovery in type 1 diabetes and islet stress.
Clinical Implications: Resource guides biomarker and target development for islet inflammation and survival, informing strategies to preserve beta-cell function in autoimmune diabetes.
Key Findings
- Generated a cell type-resolved proteomic atlas with >6000 proteins per islet endocrine cell type.
- IFN-γ exposure induced inflammatory proteomic signatures in alpha, beta, and delta cells.
- Mapped >7000 phosphosites per cell type, revealing cell-specific signaling pathways.
Methodological Strengths
- High-depth proteomics and phosphoproteomics with cell sorting enabling cell type resolution.
- Perturbational analysis with IFN-γ to model autoimmune-relevant stress.
Limitations
- Murine islet model may not fully recapitulate human islet proteomics.
- Functional validation of newly identified targets was not explored in vivo.
Future Directions: Translate atlas to human islets, integrate with single-cell transcriptomics/epigenomics, and functionally validate candidate pathways to protect beta cells.
3. Preclinical evaluation of the antitumoral efficacy of Wee1 inhibitor AZD1775 in adrenocortical carcinoma.
AZD1775 (Wee1 inhibitor) exhibited antitumor activity in ACC xenografts comparable to EDP-M and synergized in vitro with EDP-M to reduce proliferation while additively suppressing cortisol secretion. Myt1 upregulation emerged as a putative resistance mechanism in cell models, which was mitigated by EDP-M co-treatment.
Impact: Identifies Wee1 inhibition as a viable therapeutic strategy in a rare endocrine malignancy with limited options and provides a mechanistic rationale for combination with standard EDP-M.
Clinical Implications: Supports clinical translation of AZD1775 for ACC and prioritizes trials testing AZD1775 plus EDP-M to enhance efficacy, reduce cortisol excess, and potentially limit resistance.
Key Findings
- AZD1775 reduced viability and proliferation in ACC cells and showed in vivo antitumor efficacy comparable to EDP-M.
- AZD1775 synergized with EDP-M in vitro and additively suppressed cortisol secretion.
- Myt1 upregulation emerged with Wee1 inhibition in cell models; EDP-M co-treatment reversed Myt1 increase in primary ACC cells.
Methodological Strengths
- Integrated in vitro and in vivo preclinical models with mechanistic interrogation of resistance (Myt1).
- Assessment of pharmacologic combination with current standard EDP-M, including functional hormone output.
Limitations
- Single xenograft model (NCI-H295R) limits generalizability; lack of survival endpoints.
- No clinical patient data; optimal dosing/scheduling and toxicity in humans remain unknown.
Future Directions: Advance to early-phase clinical trials of AZD1775 in ACC, test biomarker-driven combinations with EDP-M, and validate Myt1 as a resistance marker and therapeutic co-target.