Biomedical subjects

Alexander Quaas

Publications and source records attributed to Alexander Quaas.

3 recordsLinked to original sources

PubMed2026

Divergent c-MYC Expression Patterns in NET and NEC: Insights from a Multicentre Cohort of 1380 Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NEN) comprise well-differentiated neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC), whose distinction is clinically critical. Although c-MYC alterations have been implicated in NEC pathogenesis, c-MYC expression across NEC subtypes and anatomical sites, as well as in NET, remains incompletely defined. We analysed c-MYC immunohistochemically in 1380 resected NEN using the Immunoreactive Score (IRS: negative 0-1, weak 2-3, moderate 4-8, strong 9-12). Overall, c-MYC positivity (IRS ≥ 2) was observed in 13.3% of NEN. Expression was detected in 43% of NEC (164/381), including strong staining in 19.4%, whereas it was rare in NET and pulmonary carcinoids (20/999; 2%; p ≤ 0.001). Within NEC, c-MYC expression was enriched in LCNEC and MiNEN compared with SCNEC and Merkel cell carcinoma (p ≤ 0.001) and occurred more often in gastroenteropancreatic than in pulmonary NEC (57.6% vs. 37.3%; p ≤ 0.001). Among NET, G3 tumours showed the highest positivity rate (6/35; 17.1%), although this was significantly lower than in NEC (p ≤ 0.001), with strong expression observed in only one NET G3 (2.9%). No association between c-MYC expression and survival was identified in either NEC or NET. Our study confirms c-MYC expression as a common event in NEC and highlights differences across histological subtypes and anatomical sites, while demonstrating its absence in most low-proliferative NET. A subset of NET G3 tumours exhibits weak to moderate c-MYC expression at levels far below those seen in NEC, suggesting that strong c-MYC positivity may support a NEC classification in borderline cases but does not represent a definitive discriminatory marker.

Humans↗

PubMed2026

A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC - as a TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

Humans↗

PubMed2026

Proteolytic activation of executioner caspase-3 and -7 regulates different physiological processes in mice.

Caspase-3 (CASP3) and caspase-7 (CASP7) are the two major executioner caspases that are proteolytically activated by upstream initiator caspases. They possess almost indistinguishable activity, which has led to the overall view that these caspases have functionally redundant roles. Here, we generate knock-in mice expressing cleavage-resistant CASP3(D175A) or CASP7(D198A). Our results show that proteolytic activation of CASP3 and CASP7 is decisive for their activity in vivo and controls redundant processes during embryonic development as combined expression of both CASP3(D175A) and CASP7(D198A) causes embryonic lethality. In adult mice, however, activation of CASP3 and CASP7 controls different processes in different tissues, without the involvement of apoptosis. While CASP7 activation is required for male fertility by controlling spermatogenesis, CASP3 activation appears crucial for lymphoid tissue development by regulating interferon signalling. Our findings shed light on emerging roles of caspases in non-apoptotic processes and provide impetus for reconsidering their involvement in physiological and pathological conditions.

Animals↗