Jacobo Kerbel's research while affiliated with Mexican Institute of Social Security and other places

Disclosure: K. Taniguchi-Ponciano: None. A. Chavez-Santoscoy: None. S. Hinojosa-Alvarez: None. J. Hernandez-Perez: None. A. Valenzuela-Perez: None. S. Vela-Patiño: None. S. Andonegui-Elguera: None. A. Cano-Zaragoza: None. F. Martinez-Mendoza: None. J. Kerbel: None. Z. Zhang: None. G. Smith: None. A. Rubenstein: None. W. Cheng: None. N. Mendelev: None. M. Amper: None. M. Zamojski: None. E. Zaslavsky: None. F.M. Ruf-Zamojski: None. S.C. Sealfon: None. M. Mercado: None. D. Marrero-Rodríguez: None. Pituitary tumors (PT) represent 20% of all intracranial neoplasms. Some behave aggressively, growing rapidly and invading surrounding tissues, with high recurrence rates and are frequently resistant to conventional therapies. We performed exome and transcriptome sequencing, as well as methylation profiling of primary and recurrent PT of the same patient. The cohort consisted of patients with GH- and gonadotropin-producing PT and a patient with an ACTH carcinoma. We sought genome evolution as well as transcriptomic and methylomic changes trough time, trying to identify molecular markers of recurrence. We performed scRNAseq to identify tumor cell populations. Compared to the primary PT, recurrent lesions showed less than 5% genomic changes in the SNV profile. The gonadotrophin-PT did not show common variants between patients or between primary and recurrent lesions. The ACTH-carcinoma showed USP8, TP53 and EGFR variants in both tumor samples, but no genomic changes between tumors despite a Ki67 of 80% in the recurrent lesion. A GH-tumor showed an AIP variant with high genetic heterogeneity. No CNV between the primary and recurrent tumors were observed. Regardless of their lineage, all PT showed different degrees of transcriptomic and methylomic heterogeneity between the primary and the recurrent lesions. Primary and recurrent tumors clustered separately from each other but together among themselves. Interestingly the differentially expressed and methylated genes in gonadotropin-producing PT are related to fatty acid biosynthesis and metabolism, GPI-anchor biosynthesis, and other metabolic pathways. ACTH-carcinoma differs significantly from the silent corticotrope in gene expression and methylation patterns. The ACTH-carcinoma showed alteration in N-Glycan biosynthesis, glycerophospholipid metabolism, purine and pyrimidine metabolism, whereas the silent corticotrope showed one carbon pool by folate, inositol phosphate metabolism, carbohydrate digestion and absorption and biosynthesis of unsaturated fatty acids. The GH-tumor showed alteration in pyruvate metabolism, propanoate metabolism, insulin secretion, and aldosterone synthesis and secretion. Our results suggest that there are several clones conforming a PT and some of them remain after surgical resection and can re-grow, this was confirmed by our scRNAseq analysis and immunofluorescence assays. We conclude that PT are genomically stable trough time, indicating that mechanisms other than somatic mutations are involved in pituitary tumorigenesis and that their biology could be driven by transcriptomically and epigenetically heterogeneous clones within the tumor itself. Presentation: Thursday, June 15, 2023

Disclosure: D. Marrero-Rodríguez: None. V. Cortes-Morales: None. K. Taniguchi-Ponciano: None. A. Valenzuela-Perez: None. S. Vela-Patiño: None. A. Cano-Zaragoza: None. F. Martinez-Mendoza: None. J. Kerbel: None. S. Andonegui-Elguera: None. J. Montesinos: None. M. Mercado: None. The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSC) and immune cells. MSC are a subset of heterogeneous cell populations characterized by the expression of CD105, CD73, and CD90 that can differentiate into chondrocytes, osteoblasts, and adipocytes in vitro. They are known to have immunomodulatory capabilities. Our aim was to isolate and characterize the immunomodulatory capabilities of MSC from pituitary tumors (PT) and non-tumoral gland as well as to describe the immune TME. We isolated and cultivated MSC from LH/FSH-PT and ACTH-PT, as well as non-tumoral pituitary glands. The MSC obtained from PT and non-tumoral gland were co-cultured in the presence of monocytes from healthy donors and their ability to transform into M0, M1 or M2 macrophages was assessed by flow cytometry. The results showed that pituitary tumors derived MSC induce an immunosuppressive M2 macrophage state, by increasing the expression of CD14 and CD206 markers, and decreasing HLA-DR. Upon co-culturing them with naïve T cells, PT MSC were capable inducing a Treg phenotype. To identify PT TME, we performed tumor whole transcriptome characterization and cellular deconvolution using CIBERSORT. Our analysis was indicative of a strong presence of M2 macrophages, TCD4+ and TCD8+ cells, which was confirmed by immunofluorescence, suggesting an immunosuppressive TME. Thus, the MSC immunosuppressive induction correlates directly with immune TME. ACTH-PT derived MSC showed a stronger anti-inflammatory activity than LH/FSH-PT. We also characterized the transcriptomic differences between non-tumoral and PT derived MSC by means of RNAseq. We found differences between the non-tumoral MSC and pituitary tumor derived MSC, but mainly between ACTH- and LH/FSH-PT derived MSC. In conclusion our data suggest that the presence of MSC influence an immunosuppressive tumor microenvironment alongside with tumor cells. Presentation: Thursday, June 15, 2023

Introduction: Despite the inherent heterogeneity of the information derived from national registries, they are a useful tool to investigate the epidemiological, clinical, biochemical and treatment outcome characteristics of low prevalence conditions such as acromegaly. Although the information provided by single-center experiences is more homogeneous, these studies usually comprise a limited number of patients and thus, frequently lack statistical power. Areas covered: Registry-based Information regarding the epidemiology, clinical presentation, biochemical and imaging diagnosis, as well as therapeutic outcome and mortality in acromegaly is critically analyzed. Expert opinion: By gathering data from multiple centers in a specific Country, these registries generate important insights into the real-life behavior of this condition, that should be considered, both, in international consensus meetings and in the design of local, Country-specific diagnostic and therapeutic strategies.

Acromegaly/giantism results from the chronic excess of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), in more than 96% of cases, due to a GH-secreting pituitary adenoma. Primary treatment of choice is transsphenoidal resection of the adenoma. More than 30% to 40% of operated cases require adjunctive forms of treatment, be it pharmacological or radiotherapeutical. The multimodal treatment of acromegaly has resulted in substantial improvements in the quality of life and life expectancy of these patients. We herein present the complex case of a patient with acromegaly due to a mammosomatotrope adenoma, with a germ-line AIP (aryl hydrocarbon receptor–interacting protein) mutation, who had a chronic and protracted course of more than 15 years during which he was treated with surgery, somatostatin receptor ligands, dopamine agonist, and the GH receptor antagonist pegvisomant. At one point, he was able to come off medications and was even found to be transiently GH-deficient, only to develop acromegaly again after a couple of years.

Over 20 years ago, Hanahan and Weinberg published a seminal review that addressed the biological processes that underly malignant transformation. This classical review, along with two revisions published in 2011 and 2022, has remain a classic of the oncology literature. Since many of the addressed biological processes may apply to non-malignant tumorigenesis, we evaluated to what extent these hallmarks pertain to the development of pituitary adenomas. Some of the biological processes analyzed in this review include genome instability generated by somatic USP8 and GNAS mutations in Cushing’s diseases and acromegaly respectively; non-mutational epigenetic reprograming through changes in methylation; induction of angiogenesis through alterations of VEGF gene expression; promotion of proliferative signals mediated by EGFR; evasion of growth suppression by disrupting cyclin dependent kinase inhibitors; avoidance of immune destruction; and the promotion of inflammation mediated by alteration of gene expression of immune check points. We also elaborate further on the existence of oncogene induced senescence in pituitary tumors. We conclude that a better understanding of these processes can help us dilucidated why pituitary tumors are so resistant to malignant transformation and can potentially contribute to the development of novel anticancer treatments.