Development of thymic tumor in [LSL:KrasG12D; Pdx1-CRE] mice, an adverse effect associated with accelerated pancreatic carcinogenesis

Liot, Sophie; Kholti, Naima El; Balas, Jonathan; Genestier, Laurent; Verrier, Bernard; Valcourt, Ulrich; Lambert, Elise

doi:10.1038/s41598-021-94566-x

Cited by 5 publications

(2 citation statements)

References 50 publications

(60 reference statements)

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“…S1D ). Thoracic lymphomas are often considered as an off-target effect of oncogenic KRAS and were excluded from subsequent survival and tumour-spectrum analyses [ 25 ]. Lymphomas were detected in both KC and KC;iASPP Δ8/Δ8 cohorts and accounted for 27% of histologically diagnosed KC tumours (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer

et al. 2023

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Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRASG12D-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRASG12D alone or KRASG12D in combination with mutant p53R172H. iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRASG12D-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRASG12D/iASPPΔ8/Δ8 tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRASG12D background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer

et al. 2023

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“…Pancreatic cancer is one of the most aggressive malignant tumors, with a 5-years survival rate of <10% ( Liot et al, 2021 ). Only 10–20% of patients are diagnosed with localized, surgically resectable pancreatic cancer ( Strobel et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Hydroxytyrosol Inhibits MDSCs and Promotes M1 Macrophages in Mice With Orthotopic Pancreatic Tumor

Wang

Yang

et al. 2021

Front. Pharmacol.

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The poor immunotherapy of pancreatic cancer is mainly due to its complex immunosuppressive microenvironment. The Mediterranean diet contributes to low cancer incidence. Hydroxytyrosol (HT) derived from olive oil has multiple health-promoting effects, but its therapeutic effect on pancreatic cancer remains controversial. Here, we evaluated the inhibitory effect of HT on mouse pancreatic cancer, and the effect of HT on the immune microenvironment. We found that HT can inhibit the proliferation of Panc 02 cells through signal transducer and activator of transcription (STAT) 3/Cyclin D1 signaling pathway. In the tumor-bearing mice treated with HT, the orthotopic pancreatic tumors were suppressed, accompanied by a decrease in the proportion of myeloid-derived suppressor cells (MDSCs) and an increase in the proportion of M1 macrophages. In addition, we found that HT inhibited the expression of immunosuppressive molecules in bone marrow (BM)-derived MDSCs, as well as down-regulated CCAAT/enhancer-binding protein beta (C/EBPβ) and phosphorylation of STAT3. Moreover, HT enhanced the anti-tumor effect of anti-CD47 antibody in vivo. HT combined with plumbagin (PLB) induced more Panc 02 cells death than HT or PLB alone. This combination therapy not only inhibited the accumulation of MDSCs, but also promoted the infiltration of CD4+ and CD8+ T cells in the tumors. In summary, HT is a potential immunomodulatory drug for the treatment of pancreatic cancer.

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Active thymus in adult with lung cancer: preliminary results from the Adult Thymic Project

Sobrero,

Patrucco,

Napoli

et al. 2024

Updates Surg

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Thymus is considered a non-functional remnant in adults, but some evidence suggest that it may harbor residual activity. Lung cancer patients represent the ideal model to study thymic residual activity, as their thymus can be easily harvested during surgery. This study was designed to confirm the presence of residual thymic activity both in adult mice (step 1) and in humans (step 2). In step 1, lung cancer was induced by activating k-ras mutation in a cohort of 20 young and adult mice. After killing, thymus and lungs were analyzed. Thymus was considered active when medullary was evident, cortico-medullary ratio was 50:50 or higher and adipose involution was present. In step 2, a cohort of 20 patients, undergoing surgery for lung cancer, had biopsy of pericardial fat pad, site of ectopic thymus. Thymus was considered present if Hassall’s bodies were detected. In mice, active thymus was detected in a high proportion of cases, without significant difference between adult and young (70% vs 44.4% respectively). Two cases without evidence of lung tumor had a fully functional thymus. In humans, ectopic thymus was detected in the pericardial fat pad in 2 cases (10.5%), confirmed by immunohistochemistry. Signs of previous thymic activity were detected in 8 additional patients. Results confirmed thymus activity in animal models and humans with lung cancer, providing the rationale for future systematic mediastinal thymic biopsy. The comprehension of interactions between thymus, lymphocytes and tumor may open a new potentially targetable perspective in lung cancer.

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Development of thymic tumor in [LSL:KrasG12D; Pdx1-CRE] mice, an adverse effect associated with accelerated pancreatic carcinogenesis

Cited by 5 publications

References 50 publications

p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer

p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer

Hydroxytyrosol Inhibits MDSCs and Promotes M1 Macrophages in Mice With Orthotopic Pancreatic Tumor

Active thymus in adult with lung cancer: preliminary results from the Adult Thymic Project

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