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Limits of Current Translational Models in ACC

Preclinical and Translational Models

Adrenocortical carcinoma (ACC) translational models are experimental systems used to study adrenal cortical tumor biology, steroidogenesis, therapeutic response, and mechanisms of progression outside routine patient care. Within ACC research, these models include established human cell lines, primary cultures, xenografts, genetically engineered or transplantable animal systems, and more recent spheroid, organoid, and engineered 3D platforms.12 They occupy a central place in preclinical research because ACC is rare, clinically heterogeneous, and difficult to study prospectively in large patient cohorts.

No available model reproduces the full biological range of human ACC. Historically dominant platforms have enabled mechanistic studies and drug screening, but many represent only a narrow subset of genotypes, steroidogenic states, and growth behaviors.34 Common limitations include incomplete adrenal lineage fidelity, restricted tumor heterogeneity, unstable or model-dependent hormone production, loss of immune and stromal context, and limited representation of metastatic evolution or treatment resistance.12

The evidence base is also constrained by the rarity of the disease. Much of the literature relies on a small number of repeatedly used platforms, retrospective characterization studies, or intervention experiments performed in single models, which limits generalizability.56 As a result, preclinical findings in ACC often suggest candidate mechanisms or vulnerabilities rather than providing robust predictions of clinical efficacy.

Biological context and why modeling is difficult

ACC is biologically heterogeneous across endocrine phenotype, differentiation state, genomic drivers, invasive behavior, and therapeutic sensitivity.78 A useful translational model therefore needs to preserve more than malignant growth alone; it may also need to reflect steroidogenic enzyme programs, hormone output, lineage markers, and clinically relevant resistant states.16

This standard is difficult to meet consistently. Across the literature, model fidelity appears strongest for focused tasks such as pathway interrogation, endocrine signaling studies, or within-model drug comparisons, and weakest when a single platform is treated as representative of ACC as a whole.42 The most reliable practical conclusion is that model choice must be matched to the biological question; the least reliable assumption is that a result in one commonly used system defines a universal ACC feature.

Major model classes and their constraints

Established human cell lines

Conventional 2D cell lines remain the most accessible and reproducible ACC platforms and support much of the field’s mechanistic and screening work.91 Their strengths are scalability, experimental control, and compatibility with genetic and pharmacologic perturbation.

However, the commonly used lines capture only a limited portion of ACC diversity. H295-derived systems are the best-characterized human steroidogenic models, but related sublines are not interchangeable: they differ in steroid output and steroidogenic enzyme expression, which can materially alter conclusions about endocrine regulation and drug response.101112 These models are therefore relatively reliable for adrenal steroidogenesis when the exact derivative is specified, but less reliable for broad disease-level inference.

Other lines raise more fundamental lineage questions. SW-13 has been widely used in signaling, invasion, and therapeutic studies, yet its adrenocortical fidelity remains debated, and its phenotype may shift through epigenetic plasticity.41314 Its use in non-ACC cell-biological experiments underscores that technical convenience does not establish adrenal cortical validity.15 In practice, SW-13 may model selected malignant behaviors, but it is a less secure surrogate for bona fide ACC biology.

Recent addition of newer patient-derived lines has broadened the available spectrum. Models such as MUC-1, JIL-2266, TVBF-7, and ZUC-1 suggest that advanced, metastatic, hormonally diverse, and treatment-resistant ACC states are more heterogeneous than older canonical systems implied.416717 This diversification is a relatively robust advance, although most newer models still require broader external validation and routine cross-platform use.

Animal and comparative models

Animal models have been important for studying adrenal tumor initiation, endocrine signaling, and some aspects of therapeutic mechanism.318 They remain useful when in vivo physiology, host endocrine regulation, or tumor development over time are central to the question.

Their limitations are longstanding. Classic rat adrenocortical carcinoma models showed selective steroidogenic defects, impaired ACTH responsiveness, and metabolic properties that diverged from normal adrenal cortex and from many human ACCs.192021 Comparative studies also show substantial species differences in adrenal enzyme systems and in the bioactivation of adrenolytic compounds, complicating extrapolation of efficacy or toxicity to humans.2223

Broader endocrine oncology literature further suggests that host background, hormonal milieu, and treatment schedule may alter in vivo readouts independently of tumor-intrinsic ACC biology.24252627 Comparative adrenal neoplasia models, including gonadectomy-associated ferret tumors, are informative about endocrine plasticity and lineage reprogramming but are only indirectly representative of human ACC.2829 Accordingly, animal findings are most reliable for mechanistic or physiologic questions within the model itself and less reliable as direct surrogates for human tumor behavior.

Xenografts and patient-derived xenografts

Xenograft systems provide an intermediate level of complexity by permitting in vivo growth, pharmacologic testing, and assessment of tumor architecture beyond monolayer culture.5 Compared with 2D systems, they may better capture growth kinetics and some aspects of treatment response.

Even so, standard xenografts usually lack the native adrenal microenvironment and cannot fully model immune interactions, endocrine regulation, or metastatic tropism. Patient-derived xenografts may better preserve histopathology and selected molecular features, but they are affected by engraftment bias, murine stromal replacement, and limited throughput.30314 Their results are therefore most dependable for comparative testing within the same model rather than for broad prediction of patient benefit.

Emerging 3D and patient-derived systems

To address the limitations of traditional models, newer spheroids, organoids, and engineered 3D constructs aim to retain more of the architecture, cell-state diversity, and endocrine behavior seen in patient tumors. Early reports indicate that some ACC 3D systems preserve cortisol secretion, patient-specific transcriptomic features, and differences between primary and metastatic disease states.3233346

These platforms are promising because they may narrow the gap between accessibility and biological fidelity. However, the evidence remains early, with variable establishment success, incomplete standardization, uncertain long-term stability, and only partial incorporation of stromal, vascular, and immune compartments.2635 At present, their most credible role is as complementary systems for hypothesis testing, comparative drug screening, and study of intra-tumoral heterogeneity rather than as definitive stand-ins for clinical ACC.

Heterogeneity and representativeness

A recurring finding across model classes is that ACC heterogeneity is underrepresented by the older, most widely used platforms. Newer patient-derived systems and paired primary-metastatic models support broader diversity in steroidogenic programs, Wnt-pathway states, resistance phenotypes, and transcriptional cell states than was captured previously.1717

This issue becomes especially important in advanced disease. Recent profiling suggests that metastatic or therapy-resistant ACC may occupy states marked by replication stress, altered epithelial-mesenchymal features, and shifting steroidogenic identity, some of which appear only partially modeled in traditional systems.833 The practical implication is methodological: reliance on a single “representative” model may miss clinically important subgroups and overstate the generality of preclinical findings.

Consequences for therapy development and biomarker research

The limitations of current models directly affect drug development. ACC platforms have identified candidate vulnerabilities involving Wnt/β-catenin signaling, ER stress, ferroptosis-related biology, DNA-damage response, and drug-resistance pathways, but treatment effects often vary substantially across models.363738398 These findings are useful for prioritizing therapeutic hypotheses, but single-model efficacy is not a reliable predictor of patient-level responsiveness.

The same caution applies to biomarker work. Proposed mediators of resistance or sensitivity, including transporters, lipid-metabolic programs, microRNAs, and cell-state transitions, appear to be context-dependent and may evolve under treatment pressure.404142 Biomarker claims are therefore most credible when reproduced across multiple steroidogenic and non-steroidogenic, treatment-sensitive and resistant, and primary- and metastatic-derived systems.

Role in ACC research

Taken together, the literature supports a plural rather than singular modeling strategy. Combining established cell lines with xenografts, patient-derived 3D systems, and selected animal models may better approximate the biological range of ACC than reliance on any single platform.412 This conclusion is better supported than claims that any one model class has solved the translational gap.

Important gaps remain, particularly in modeling immune interactions, adrenal microenvironmental influences, metastatic dissemination, and longitudinal evolution during therapy.26 Current translational models are therefore best understood as tools for mechanism generation, comparative testing, and hypothesis prioritization, rather than as definitive predictors of clinical outcome in ACC.

Included Articles

  • PMID 170296: An ex vivo slice model of human adrenocortical tissue showed lower and more variable transmembrane potentials in adrenocortical tumors than in non-tumor cortex, with most tumor samples showing little fluorogenic steroidogenic response to ACTH or cyclic AMP except a virilizing adenoma.43
  • PMID 172310: This study characterizes the rat Snell adrenocortical carcinoma 494 cell suspension model, showing intact viable tumor cells can be prepared without enzymatic digestion and that these cells display hormone-stimulated cyclic AMP responses, including marked ACTH sensitivity and reduced hormonal specificity.44
  • PMID 216596: Using isolated cells from the Snell rat adrenocortical carcinoma 494 model, this study found minimal ACTH stimulation of pregnenolone synthesis, marked rescue with 25-hydroxycholesterol, and very low tumor-cell cholesterol and cytochrome P-450 content, supporting substrate-limited steroidogenesis in this experimental ACC system.45
  • PMID 225158: Using isolated rat adrenocortical carcinoma cells as an experimental model, this study found that ACTH induces a transient rise in cGMP followed by cGMP-specific phosphodiesterase activation, suggesting feedback regulation of cGMP degradation during steroidogenic signaling.46
  • PMID 226350: This rat Snell adrenocortical carcinoma model showed limited ACTH-stimulated steroidogenesis that appeared largely constrained by cholesterol availability, with very low cytosolic cholesterol ester hydrolase activity and preferential use of HDL-derived cholesterol. The tumor cells mainly produced deoxycorticosterone, consistent with low mitochondrial 11β-hydroxylase activity relative to cholesterol side-chain cleavage activity.47
  • PMID 637320: This study characterizes the transplantable rat adrenocortical carcinoma 494 model as a corticosterone-secreting, relatively ACTH-insensitive tumor with ultrastructural and biochemical features compared against normal adrenal tissue. It establishes baseline morphology, organelle composition, lipid handling, and host adrenal atrophy for later therapeutic experiments.18
  • PMID 20888: Using isolated adrenocortical carcinoma cells, this study describes abnormal ACTH signaling with increased cyclic GMP but no corresponding rise in cyclic AMP, protein kinase activity, or corticosterone synthesis. The findings support a tumor cell model of defective cyclic nucleotide–dependent kinase regulation of steroidogenesis.48
  • PMID 2156720: Using the human adrenocortical carcinoma cell line SW-13, this study found specific, saturable, time- and temperature-dependent heparin binding, with Scatchard analysis suggesting high-affinity and low-affinity binding sites. The work supports SW-13 as a translational model for studying cell-surface ligand interactions and growth modulation in ACC-derived cells.49
  • PMID 2875690: Using isolated rat adrenocortical carcinoma cells, the study describes alpha2-adrenergic signaling that positively couples to particulate guanylate cyclase and cyclic GMP while negatively coupling to adenylate cyclase and cyclic AMP. The cyclic GMP response required calcium and was blocked by yohimbine, supporting this ACC cell system as a model for signal-transduction biology.50
  • PMID 2892695: In isolated rat adrenocortical carcinoma cells, phorbol ester activation of protein kinase C suppressed atrial natriuretic factor receptor-coupled membrane guanylate cyclase activity and reduced ANF-stimulated cyclic GMP accumulation, while inactive phorbol analogs did not. These findings define a signaling interaction in a rat ACC cell model relevant to steroidogenic signal transduction.51
  • PMID 2903736: Using rat adrenocortical carcinoma cells as a signaling model, this study found that protein kinase C activation by phorbol ester suppresses alpha2-adrenergic agonist-stimulated cyclic GMP production. The findings also suggest that alpha2-receptor coupling to guanylate cyclase is indirect in intact ACC cells rather than direct in cell-free membranes.52
  • PMID 4366105: Using the Snell adrenocortical carcinoma 494 model, this study describes ultrastructural and metabolic differences from normal adrenal cortex, including abnormal mitochondrial number and cristae, markedly impaired corticosterone synthesis, reduced 11β-hydroxylation capacity, and selective defects in mitochondrial substrate oxidation.19
  • PMID 4390412: A transplantable rat adrenocortical carcinoma model produced corticosterone at much lower levels than normal adrenal tissue and showed marked ACTH unresponsiveness. The study identified impaired cyclic AMP regulation and additional defects in steroidogenic responsiveness, supporting this model for mechanistic investigation of ACC biology.20
  • PMID 6115633: Using a spontaneous adrenocortical carcinoma model, this cell-free biochemical study identified an ACTH-responsive particulate guanylate cyclase distinct from soluble guanylate cyclase. The response required calcium, was not reproduced by calcium alone, and was not stimulated by sodium nitroprusside or ascorbic acid.53
  • PMID 6127983: This rat adrenal and rat adrenocortical carcinoma study identified an ACTH-responsive particulate guanylate cyclase distinct from soluble guanylate cyclase, with different kinetic and pharmacologic properties and a proposed link to steroidogenesis. In the carcinoma model, particulate activity was lower and soluble activity higher than in normal adrenal tissue.54
  • PMID 7457928: In a rat adrenocortical carcinoma model, aminoglutethimide and o,p’-DDD markedly reduced corticosterone production and induced mitochondrial and lipid structural changes, but had little effect on tumor growth. The study illustrates how transplantable animal models can dissect steroidogenic and ultrastructural drug effects relevant to ACC biology.55
  • PMID 9118466: This mechanistic laboratory study examined adrenal proteins covalently bound by a reactive mitotane intermediate and found similar electrophoretic adduct patterns across bovine, canine, and human adrenal preparations. The cross-species similarity supports canine and bovine adrenal systems as translational models for studying mitotane mechanism and designing improved ACC-directed compounds.23
  • PMID 11078430: Using the SW-13 adrenocortical carcinoma cell line, this study found secretion of endothelin-1 and adrenomedullin with corresponding mRNA expression, while several other neuropeptides were not detected. The findings support SW-13 as a translational model for studying ACC peptide biology and possible autocrine or paracrine signaling.56
  • PMID 11139773: In the H295R human adrenocortical carcinoma cell model, EGF and bFGF increased 3beta-HSD type II mRNA and suppressed CYP17 mRNA, with CaMK II and MAPK signaling implicated in this differential steroidogenic regulation. The study supports H295R as a translational platform for dissecting ACC-related steroidogenesis pathways.11
  • PMID 12697691: In the H295R adrenocortical carcinoma cell model, epidermal growth factor increased cortisol output and type II 3beta-hydroxysteroid dehydrogenase expression, with promoter studies indicating a Stat5-dependent transcriptional mechanism. The study supports H295R as a translational system for dissecting steroidogenic signaling relevant to ACC biology.12
  • PMID 13167090: A murine post-castration adrenocortical carcinoma model demonstrated measurable glucocorticoids in all assayed tumors, despite prior recognition mainly of sex steroid secretion. Tumor tissue showed lower glucocorticoid concentration than normal adrenal tissue by weight, but greater total hormone burden per animal.57
  • PMID 14231157: In a transplanted rat adrenocortical carcinoma model, investigators found loss of both components required for 11 beta-hydroxylation, while 21-hydroxylation, C-5 isomerization, and C-3 oxidation remained intact. The work illustrates selective steroidogenic pathway disruption in ACC model systems.21
  • PMID 14715709: A rodent preclinical study developed a StAR-expressing murine tumor model and showed that DNA prime plus vaccinia boost vaccination against StAR generated antigen-specific T-cell responses and reduced growth of StAR-expressing tumors. The work identifies StAR as a potential immunotherapeutic target in ACC.58
  • PMID 15688364: A cisplatin-resistant adrenocortical carcinoma cell line, D43/86RCIS, overexpressed MRP2 and showed cross-resistance to cisplatin and carboplatin, supporting MRP2 as a mechanistic model of platinum resistance. The study frames MRP2 inhibition as a translational strategy to restore platinum-DNA adduct formation and chemosensitivity.40
  • PMID 17337116: This review highlights the scarcity of suitable ACC models and describes gonadotropin-responsive murine systems, including gonadectomized transgenic inha/Tag mice, used to study adrenal tumor initiation, progression, and links between ectopic LHR expression and GATA-4/GATA-6 biology.3
  • PMID 18000308: This comparative study shows that the two widely used ACC-derived H295 sublines are not interchangeable: NCI-H295A is relatively mineralocorticoid-producing, whereas NCI-H295R is more androgenic because of lower HSD3B2 and higher 17,20-lyase activity. The findings refine how these cell models should be selected for translational studies of adrenal steroidogenesis.10
  • PMID 18034334: An ex vivo precision-cut adrenal slice model showed marked species differences in CYP11B1-dependent bioactivation and irreversible binding of the adrenocorticolytic lead compound 3-MeSO2-DDE, with highest binding in mouse and hamster and minimal binding in rat and guinea pig. These findings support cautious species selection for translational toxicology and drug-development studies relevant to ACC.22
  • PMID 18544621: In the H295R adrenocortical carcinoma cell model with CTNNB1 and TP53 alterations, the Tcf/beta-catenin antagonist PKF115-584 reduced beta-catenin-dependent transcription, suppressed proliferation, decreased S-phase entry, and increased apoptosis. These findings support Wnt/beta-catenin inhibition as a translational therapeutic strategy requiring in vivo evaluation and toxicity consideration.36
  • PMID 18670617: In ACC cell lines and limited tissue samples, IGF-IR was highly expressed, IGF-I stimulated proliferation, and rosiglitazone inhibited growth by suppressing downstream PI3K/Akt and ERK1/2 signaling without changing IGF-IR levels. The findings support IGF-IR pathway dependence as a translational therapeutic target in preclinical ACC models.59
  • PMID 22056412: This review summarizes ACC xenograft models for preclinical drug testing, comparing subcutaneous and orthotopic approaches, relevant endpoints, imaging and hormonal follow-up methods, and pharmacology limitations. It emphasizes that fresh tumor explants and molecular characterization may better preserve tumor phenotype and improve translational relevance.5
  • PMID 22407999: This preclinical study used NCIh295 ACC cells and xenografts to test liposomal doxorubicin strategies, including IGF1R-targeted immunoliposomes. Targeted and pegylated liposomal formulations reduced xenograft tumor size after a single treatment and support liposomal drug delivery as a translational therapeutic concept in ACC.60
  • PMID 22999104: A quantitative high-throughput screen of 2,816 approved compounds in ACC cell lines identified multiple antiproliferative hits, with bortezomib, ouabain, methotrexate, and pyrimethamine showing activity in monolayer and 3-dimensional multicellular aggregate models at clinically achievable concentrations. The study illustrates drug-repurposing and 3D cell-model validation as translational strategies for rare ACC.9
  • PMID 23406775: This study established the first pediatric ACC xenograft model, derived from a TP53-mutant tumor and shown to retain the primary tumor’s histopathologic and molecular features. In drug testing, the model showed strong cisplatin sensitivity and growth inhibition with topotecan, supporting its use for translational therapeutic screening in pediatric ACC.30
  • PMID 25038520: Using the HAC15 adrenocortical carcinoma cell model, pioglitazone increased CYP11B2 mRNA yet reduced AngII-induced CYP11B2 protein and aldosterone output, while promoting AngII-induced CYP11B1 expression and cortisol production. The findings implicate unfolded protein response signaling with DDIT3 and phospho-eIF2α as a translational mechanism affecting steroidogenesis.61
  • PMID 25619516: A canine cortisol-secreting adrenocortical tumor study found PI3K pathway activation in carcinomas but not adenomas, without recurrent PTEN or PIK3CA coding mutations or increased IGF-II/IGF1R expression. ERBB2 and the differentiation markers ID1 and ID2 emerged as candidate therapeutic or prognostic signals in this comparative model.62
  • PMID 26994514: This preclinical study compares IGF1R-targeted antibody approaches with liposomal doxorubicin across ACC xenograft models and shows model-dependent treatment effects linked to differing IGF1R and IGF2 expression. The findings support use of multiple xenograft systems to study heterogeneity and develop predictive biomarkers for IGF1R-directed therapy.31
  • PMID 27188282: Using the SW13 adrenocortical carcinoma cell line, this study identifies epigenetically maintained SW13- and SW13+ subtypes with differing biology: SW13- cells are more proliferative, whereas SW13+ cells show greater metastatic potential. HDAC1 inhibition promotes conversion toward the SW13+ phenotype with BRM re-expression and histone modification changes, highlighting a model of ACC heterogeneity and epigenetic plasticity.13
  • PMID 27550961: This study evaluates liposomal variants of the standard EDP-M regimen in ACC xenograft models and reports heterogeneous antitumor activity across SW-13 and SJ-ACC3, with improved off-target histologic profiles and preliminary compassionate-use data suggesting better tolerability. It also explores circulating microRNA-210 as an early translational treatment-monitoring biomarker.63
  • PMID 27631436: In the NCI-H295R ACC cell model, bortezomib and carfilzomib showed synergistic anti-proliferative activity with mitotane, with complementary modulation of ER-stress pathways and reduced steroid secretion. The study proposes clinically available proteasome inhibitors as translational combination candidates for future ACC trials.37
  • PMID 27764813: This study shows that commonly used ACC preclinical models incompletely capture tumor heterogeneity, with substantial clone-dependent differences in NCI-H295R xenografts and questionable adrenocortical fidelity of SW-13. It introduces a new patient-derived model, MUC-1, that retains cortical markers, cortisol production, and resistance to EDP-M, potentially improving translational relevance.4
  • PMID 29112114: In the H295R adrenocortical carcinoma cell model, PELP1 was expressed in ACC tissues and cells and mediated estrogen receptor alpha and IGF1R cross-talk through a PELP1/ERalpha/IGF1R/Src complex, promoting ERK activation, Cyclin D1 expression, and proliferation. PELP1 knockdown reduced basal and ligand-stimulated growth signals, supporting it as a translational candidate target.64
  • PMID 29474877: In the H295R ACC cell model, the GRP78/BiP inhibitor HA15 induced unfolded protein response signaling, reduced proliferation and steroidogenesis, and showed synergistic activity with mitotane. The study supports convergent ER stress activation as a translational therapeutic strategy for ACC.38
  • PMID 30651077: Using the SW13 adrenocortical carcinoma cell line as an epigenetically plastic model, HDAC inhibition altered glycome-related gene expression and glycosylation patterns while increasing invasive features and reducing paclitaxel sensitivity. The study highlights a translational platform for investigating epigenetic regulation of ACC tumor behavior and treatment response.14
  • PMID 30918109: A preclinical study identified miR-431 as underexpressed in stage IV ACC resistant to adjuvant therapy and showed that restoring miR-431 in ACC cell models lowered doxorubicin and mitotane IC50 values, increased apoptosis, and was linked to ZEB1-mediated reversal of epithelial-mesenchymal transition.41
  • PMID 32184394: Preclinical ACC and adrenal cortex models show marked susceptibility to GPX4-inhibitor-induced type II ferroptosis, linked to active steroidogenesis and abundant peroxidizable lipids. Ketoconazole reverses this effect, whereas mitotane increases lipid peroxidation without inducing ferroptotic cell death.39
  • PMID 32343624: This preclinical pharmaceutical study developed spray-dried mitotane liposomes for oral use and found improved ex vivo intestinal permeation and in vivo relative bioavailability compared with free-drug formulations. The work addresses a translational limitation of mitotane, namely poor solubility and low oral bioavailability.65
  • PMID 32550272: This review summarizes contemporary human ACC preclinical models, including NCI-H295, pediatric SJ-ACC3, MUC-1, and CU-ACC1/CU-ACC2 cell line and patient-derived xenograft platforms. It highlights how newer models better capture ACC heterogeneity, steroidogenic phenotypes, molecular alterations, and differential drug sensitivity relevant to translational therapy development.1
  • PMID 32751066: This preclinical study identifies astemizole as an inhibitor of Patched-mediated drug efflux in ACC models and shows that low-dose astemizole enhances doxorubicin cytotoxic, proapoptotic, antiproliferative, and anticlonogenic effects in H295R cells, supporting Patched as a translational target for overcoming chemotherapy resistance.66
  • PMID 34096882: This commentary highlights establishment of the JIL-2266 ACC cell line from a metastatic, cortisol-secreting tumor with germline MUTYH alteration, TP53 mutation, and signature 18 genomic features. It emphasizes how genetically diverse, bona fide ACC models can support translational studies of steroidogenesis, drug sensitivity, tumor microenvironment, and immunotherapy response.16
  • PMID 34285285: Using Men1 heterozygous mice as an early adrenal tumorigenesis model, this study identified downregulation of miR-486-3p and showed that restoring miR-486-3p in human ACC cell lines reduced proliferation, FASN expression, and palmitic acid synthesis. These findings support a translational link between early miRNA dysregulation and lipid metabolism in ACC biology.67
  • PMID 35563746: This study compares established ACC cell lines with a newly developed line, TVBF-7, showing distinct driver-gene alterations, steroidogenic programs, receptor expression, electrophysiologic properties, and hormone secretion patterns. The findings support use of diversified cell-line panels to model clinically relevant endocrine heterogeneity in ACC preclinical research.7
  • PMID 36151566: High-throughput screening in ACC cell lines identified synergistic antitumor activity of the MELK inhibitor OTS167 plus the CDK inhibitor RGB-286638, with validation across proliferation, invasion, spheroid, clonogenic, mechanistic, and xenograft models. The study links target overexpression to adverse clinical features and supports clinical translation of this combination.68
  • PMID 36320101: Using the HAC15 human adrenocortical carcinoma cell model, this study shows that mTOR inhibition suppresses angiotensin II-driven aldosterone and cortisol production, with associated reductions in steroidogenic enzyme expression and signaling through Raptor and Rictor complexes.69
  • PMID 36400581: This study reports fine needle aspiration–based generation of patient-derived 3-dimensional endocrine organoids that included adrenocortical carcinoma cases. ACC organoids showed morphologic features of endocrine tumor microenvironment, abundant secretory granules on electron microscopy, and maintained cortisol secretion, supporting their use as translational in vitro models.32
  • PMID 36646964: This translational study links advanced ACC to increased CAIX and reduced CAIII expression in tumor tissue and in coculture models with visceral adipose stem cells, supporting metabolic crosstalk between ACC and its local adipose microenvironment and suggesting carbonic anhydrases as investigational therapeutic targets.70
  • PMID 36831394: This preclinical cell-line study found that curcumin reduced ACC cell viability and migration and induced apoptosis in H295R, SW13, and MUC-1 models. It also identified metabolic rewiring toward glutamine utilization after curcumin exposure, suggesting combination strategies with glutamine metabolism inhibition as a translational therapeutic hypothesis.71
  • PMID 37221428: This study links ACC to altered apoptosis signaling by showing CHCHD2 upregulation and BAX downregulation in tumor tissue, while CHCHD2 silencing in SW13 cells reduced viability and invasion and increased apoptosis. The findings support CHCHD2 as a translational candidate target, although prognostic associations and mechanism remain uncertain.72
  • PMID 37296836: This review summarizes current ACC preclinical platforms, including cell lines, primary cultures, spheroids, organoids, xenografts, and genetically engineered mouse models, emphasizing recent expansion beyond the historically limited model repertoire. It highlights tradeoffs in tumor microenvironment fidelity, genetic heterogeneity, reproducibility, and public availability that shape translational research and drug development.2
  • PMID 37867801: In ACC cell models, early low-dose exposure to mitotane, doxorubicin, or cisplatin increased ACSL4 and ABCG2 expression and was associated with greater viability, proliferation, and drug efflux. Public transcriptomic data also linked mitotane-resistant HAC15 cells to higher ACSL4 and ABCG2 expression, supporting these pathways as translational resistance mechanisms.42
  • PMID 39528354: This preclinical study identifies a FLNA-Wee1 regulatory axis in ACC, showing that low FLNA is associated with higher Wee1 expression and that Wee1 inhibition with AZD1775 or Wee1 silencing reduces ACC cell proliferation and viability. FLNA loss also appears to enhance AZD1775 sensitivity, supporting Wee1 as a translational therapeutic target candidate.73
  • PMID 39554059: Single-nuclei RNA sequencing of primary and metastatic ACC identified tumor-cell heterogeneity, including an adrenal cortex cluster marked by replication stress and DNA damage response programs. Functional testing in an ACC cell line and newly derived hormonally active patient-derived tumor organoids showed ATR sensitivity, supporting translational investigation of this vulnerability.8
  • PMID 39677699: This preclinical study shows that ACC cell lines can actively internalize iron oxide nanoparticles in a concentration- and time-dependent manner, with intracellular localization in cytoplasm and vesicles. Uptake was reduced in multicellular models because endothelial cells and monocytes also absorbed nanoparticles, highlighting a translational barrier to ACC-targeted nanoparticle delivery.74
  • PMID 39803746: This preclinical study reports that β-elemene suppresses ACC cell viability, proliferation, and migration while promoting apoptosis in SW-13 and NCI-H295R models, with supportive subcutaneous xenograft findings. The proposed mechanism involves upregulation of miR-486-3p and negative regulation of NPTX1, identifying a candidate therapeutic axis for further translational study.75
  • PMID 40488953: This review identifies patient-derived organoids as emerging preclinical models for endocrine cancers including adrenocortical carcinoma, highlighting their ability to preserve parental tumor genotype, phenotype, heterogeneity, and drug-sensitivity features. It also notes an ACC organoid culture system and emphasizes the lack of standardized protocols across tumor types.6
  • PMID 41085008: This study presents an automated microfluidic single-spheroid platform using ACC spheroids for continuous extracellular vesicle collection and isolation, enabling transcriptomic profiling at the individual spheroid level. In this model, β-catenin inhibition reduced EV-derived miR-139-5p and miR-483-5p, supporting investigation of tumor heterogeneity and biomarker-linked drug response.35
  • PMID 41310103: Using 2D and 3D ACC models derived from primary, regional metastatic, and distant metastatic disease, the study links nonmetastatic spheroids to canonical Wnt activity and metastatic models to noncanonical Wnt signaling, cytoskeletal remodeling, HOX program changes, and variable stemness features. It also shows these phenotypes can shift with therapeutic or differentiation-modulating treatments.33
  • PMID 41528016: This study establishes ZUC-1, a new patient-derived 2D and 3D ACC model from an advanced primary tumor with synchronous bone, liver, and lung metastases. The model shows distinctive multihormonal secretion, steroidogenic gene expression, genomic alterations, and heterogeneous Wnt-pathway activation, supporting translational studies in advanced ACC.17
  • PMID 41542508: This preprint describes patient-derived 3D ACC tumor constructs built from clinical biospecimens in synthetic extracellular matrix, preserving proliferation, cortisol production, ACC marker expression, and patient-specific transcriptomic features. The platform was used to test standard chemotherapy, targeted agents, and natural-killer-cell immunotherapy, highlighting a potential translational model for therapeutic screening.34
  • PMID 4352748: A 1973 multistrain mouse study of chronic Enovid exposure found markedly strain-specific endocrine and neoplastic effects, with pituitary and reproductive tract lesions predominating and no clear induction of adrenocortical carcinoma. Its relevance to ACC is indirect but supports the note’s emphasis that rodent endocrine tumor responses depend heavily on host background and may not map cleanly onto human ACC.24
  • PMID 4719016: A 1973 rat tumor study argued that thymic, adrenal, hepatic, and metabolic changes in tumor-bearing animals act as inherent experimental factors that can alter interpretation of in vivo results. While indirect to ACC, it supports the note’s emphasis that host endocrine physiology and animal background can materially shape translational model readouts.25
  • PMID 6596030: A 1984 rat study found that several anticancer drugs could acutely activate the pituitary-adrenal axis, but repeated treatment led to tolerance for most agents, whereas hydroxyurea retained ACTH-dependent adrenocortical activation and showed stronger effects in tumor-bearing animals. Although indirect to ACC, this supports caution that adrenal and endocrine endpoints in animal cancer models may be shaped by host-state and treatment-schedule effects.26
  • PMID 13699763: A 1961 A x C rat study of chemically induced liver carcinogenesis found that sex, adrenal status, and exogenous androgenic or anabolic hormones altered tumor incidence, cirrhosis, and tumor differentiation. While indirect to ACC, it adds nuance to the note’s discussion of endocrine context and host-state dependence in older animal cancer models.76
  • PMID 19784476: In a BALB/c Ehrlich tumor model, cyhalothrin exposure increased corticosterone, suppressed macrophage activity, and was associated with greater tumor growth, suggesting that host stress-endocrine and immune responses can shape experimental cancer outcomes. While indirect to ACC, the study reinforces caution in interpreting adrenal-related readouts in tumor-bearing animals as purely tumor intrinsic.27
  • PMID 24906927: Ferret gonadectomy-associated adrenocortical tumors showed decreased expression of several adrenal steroidogenic genes but increased cytochrome b5, aromatase, and inhibin, consistent with androgen-producing and gonadal-like differentiation. This extends the note’s discussion of hormone-driven comparative models by showing a distinct adrenal tumor phenotype that is relevant but not directly representative of typical human ACC.29
  • PMID 824591: An older rat DMBA study suggests that host metabolic modulation can change carcinogen-driven tumor outcomes without equivalently altering adrenal injury. Coumarin pretreatment suppressed mammary carcinogenesis but did not protect against DMBA-induced adrenocortical necrosis, underscoring the indirect and compartment-specific nature of some endocrine-toxicologic findings relevant to ACC modeling.77
  • PMID 15560848: A 2004 live-cell imaging study used SW-13 cells as a vimentin-free background for tracking nuclear particles and microspheres, highlighting the line’s utility for general cell-biological experiments rather than ACC-specific modeling. In the context of ACC translational models, this indirectly supports caution about treating SW-13 findings as evidence for adrenal cortical biology.15
  • PMID 18587089: A ferret comparative model showed that gonadectomy-associated adrenocortical neoplasms frequently upregulate cytochrome b5 and may acquire androgen-producing, gonadal-like steroidogenic features. For ACC modeling, this mainly adds an indirect caution that endocrine output in animal adrenal tumors can reflect species- and host-state-specific differentiation programs rather than human ACC biology per se.28

References

Footnotes

  1. Contemporary preclinical human models of adrenocortical carcinoma.. Curr Opin Endocr Metab Res. 2019. PMID: 32550272. Local full text: 32550272.md ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7

  2. Preclinical Models of Adrenocortical Cancer.. Cancers (Basel). 2023. PMID: 37296836. Local full text: 37296836.md ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7

  3. Adrenocortical tumorigenesis, luteinizing hormone receptor and transcription factors GATA-4 and GATA-6.. Mol Cell Endocrinol. 2007. PMID: 17337116. Local full text: 17337116.md ↩ ↩2 ↩3

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