Introduction: Early stages of prostate cancer (PCa) are commonly treated with surgery and androgen-deprivation therapy, but PCa can turn castration resistant due to pre-existing stem cell-like cells which might re-initiate tumor growth and lead to metastasis. Previously, it has been shown that human tumors express high levels of Cripto, an oncofetal protein, for this reason our hypothesis is that Cripto might play a role in PCa initiation and progression. We aim to study its oncogenic features in GEMMs models that are representative of early and late metastatic PCa. Methods: We performed conditional Cripto (CRIPTOflox/flox) knock out on N (Nkx3.1CreERT2, R26 LSL-YFP/LSL-YFP), NP (Nkx3.1CreERT2; Ptenflox/flox, R26 LSL-YFP/LSL-YFP) and NPK (Nkx3.1CreERT2; Ptenflox/flox; KrasLSL-G12D/+, R26 LSL-YFP/LSL-YFP) to generate respectively NC, NPC and NPKC. N animals mirror normal epithelium, whereas first stage of the disease, high-grade prostatic intraepithelial neoplasia (PIN)/carcinoma lesions with local invasive epithelium, are seen in NP. More advanced stage with invasive prostate adenocarcinoma with metastasis are developed in NPK. In vivo experiments’ workflow was the following: 8-weeks old mice were castrated and induced one month later with 5 daily injections of tamoxifen, after 2.5 weeks, animals were weekly treated with testosterone (10 weeks). Organoids were generated from YFP+/− single cell population recovered by FACS sorting. Results: Histopathological evaluation of newly generated NPC and NPKC showed presence of mPIN (100%, nNPC= 6, nNPKC=2), with a dominant cribriform morphology. NPKC additionally, features invasive PCa with an extent dominant pattern of 100%, showing portions with dense stroma forming whorl-like structures and occasional sheet-like accumulations of polygonal in stroma of regions with mPIN. In general, NPC and NPKC feature a more reactive stroma with a mild/moderate inflammation compared to the published models. OrganoidsYFP+ recapitulate molecular prostate tissue features, expressing luminal and basal markers. Organoids’ morphology varies consistently: N and NC are low in density and present a more cystic morphology, which is consistent with low-grade PIN phenotypes, whereas NP and NPK organoids are solid and denser which mimics an oncogenic transformation. In general, NC, NPC and NPKC organoids present a higher percentage of hollow organoids compared to N, NP and NPK respectively. Conclusions: NPC and NPKC phenotype specifically, showed important stromal alterations suggesting that Cripto might play a role not only on the epithelial compartment as well as in the stroma. For this reason, studies on secreted Cripto inhibition with ALK4-Fc are on-going. Our results show that organoids are an efficient in vitro model replicating different phenotypes seen in vivo. Citation Format: Elisa Rodrigues Sousa, Eugenio Zoni, Mario Scarpa, Marta De Menna, Allen Abey Alexander, Simone De Brot, George N. Thalmann, Marianna Kruithof-de Julio. Generation of a new mouse model to study the role of oncofetal Cripto in aggressive lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A044.
Novel therapeutic strategies are needed for paediatric patients affected by Acute Myeloid Leukaemia (AML), particularly for those at high-risk for relapse. MicroRNAs (miRs) have been extensively studied as biomarkers in cancer and haematological disorders, and their expression has been correlated to the presence of recurrent molecular abnormalities, expression of oncogenes, as well as to prognosis/clinical outcome. In the present study, expression signatures of different miRs related both to presence of myeloid/lymphoid or mixedlineage leukaemia 1 and Fms like tyrosine kinase 3 internal tandem duplications rearrangements and to the clinical outcome of paediatric patients with AML were identified. Notably, miR-221-3p and miR-222-3p resulted as a possible relapse-risk related miR. Thus, miR-221-3p and miR-222-3p expression modulation was investigated by using a Bromodomain-containing protein 4 (BRD4) inhibitor (JQ1) and a natural compound that acts as histone acetyl transferase inhibitor (curcumin), alone or in association, in order to decrease acetylation of histone tails and potentiate the effect of BRD4 inhibition. JQ1 modulates miR-221-3p and miR-222-3p expression in AML with a synergic effect when associated with curcumin. Moreover, changes were observed in the expression of CDKN1B, a known target of miR-221-3p and miR-222-3p, increase in apoptosis and downregulation of miR-221-3p and miR-222-3p expression in CD34 + AML primary cells. Altogether, these findings suggested that several miRs expression signatures at diagnosis may be used for risk stratification and as relapse prediction biomarkers in paediatric AML outlining that epigenetic drugs, could represent a novel therapeutic strategy for high-risk paediatric patients with AML. For these epigenetic drugs, additional research for enhancing activity, bioavailability and safety is needed.
Introduction: Prostate cancer (PCa) at its early stages is treated with surgery or androgen-deprivation therapy, but PCa can turn castration resistant possibly due to pre-existing stem cell-like cells that reinitiate tumor growth and lead to metastasis. Given that human tumors express high levels of the oncofetal Cripto, our hypothesis is that Cripto might play a role in PCa initiation and progression, so we conditionally knock out Cripto in GEMMs models representative of early and late metastatic PCa to study its oncogenic potential. Methods: Conditional Cripto knock out (CRIPTOflox/flox) was performed on N (Nkx3.1CreERT2, R26 LSL-YFP/LSL-YFP), NP (Nkx3.1CreERT2; Ptenflox/flox, R26 LSL-YFP/LSL-YFP) and NPK (Nkx3.1CreERT2; Ptenflox/flox; KrasLSL-G12D/+, R26 LSL-YFP/LSL-YFP) to generate respectively NC, NPC and NPKC. Normal epithelium is mirrored by N animals, whereas first stage of the disease, high-grade prostatic intraepithelial neoplasia (PIN)/carcinoma lesions with local invasive epithelium, are seen in NP. The advanced stage of PCa with metastasis formation is developed in NPK. In vivo experiments presented the following workflow: 8-weeks old mice were castrated and induced one month later with 5 daily injections of tamoxifen, after 2.5 weeks animals were weekly treated with testosterone (10 weeks). Single cells were isolated from prostate tissue and the YFP+/− population recovered by FACS sorting and cultured as organoids. Results: Published PCa models N, NP and NPK were confirmed. The histopathological evaluation of newly generated NPC and NPKC shows presence of mPIN (100%, nNPC= 6, nNPKC=5), with a dominant cribriform morphology. NPKC presents invasive PCa with an extent dominant pattern of 100%. Invasive portions in NPKC present dense stroma forming whorl-like structures and occasional sheet-like accumulations of polygonal in stroma of regions with mPIN. Compared to the published models, NPC and NPKC feature a more reactive stroma with a mild/moderate inflammation. OrganoidsYFP+ recapitulate molecular prostate tissue features, expressing luminal and basal markers. Organoids’ morphology varies consistently: N and NC organoids present a more cystic morphology, with lower densities which is consistent with low-grade PIN phenotypes, whereas NP and NPK organoids are smaller and denser which mimics an oncogenic transformation. In general, NC, NPC and NPKC organoids present a higher percentage of hollow organoids compared to N, NP and NPK respectively. Conclusions: Histopathological evaluation of NPC and NPKC phenotype specifically, showed important stromal alterations suggesting that Cripto might play a role not only on the epithelial compartment as well as in the stroma. For this reason, studies on secreted Cripto inhibition with ALK4-Fc are on-going. Our finding support that organoids are an efficient in vitro model replicating different phenotypes seen in vivo. Citation Format: Elisa Rodrigues Sousa, Eugenio Zoni, Mario Scarpa, Marta De Menna, Allen Abey Alexander, Simone De Brot, George N. Thalmann, Marianna Kruithof-de Julio. A new transgenic mouse model to explore the role of Cripto signaling in lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 22.
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