Biology subjects

Weigel, R.

Publications and source records attributed to Weigel, R..

4 recordsLinked to original sources

bioRxiv2023

Contrasting roles of different mismatch repair proteins in basal-like breast cancer

The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely undefined. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS). MSH2 expression is frequently elevated due to genomic amplification or gain-of-expression in BLBC, which results in increased MSH2 protein to pair with MSH6 (collectively referred to as MutS). Genetic deletion of MSH2 or MLH1 results in a contrasting phenotype in metastasis, with MSH2-deletion leading to reduced metastasis and MLH1-deletion to enhanced liver or lung metastasis. Mechanistically, MSH2 - but not MLH1 - binds to the promoter region of interferon receptor 1 (IFNAR1) and suppresses its expression in BLBC. Deletion of MSH2 initiates a chain of immune reactions via the upregulation of IFNAR1 expression and the activation of type 1 interferon signaling, which explains a highly immune active tumor microenvironment in tumors with MSH2-deficiency. Our study supports the contrasting functions of MSH2 and MLH1 in BLBC progression and metastasis due to the differential regulation of IFNAR1 expression, which challenges the paradigm of the MMR pathway as a universal tumor suppressive mechanism.

cancer biology↗

bioRxiv2023

Active Gαi/o mutants accelerate breast tumor metastasis via the c-Src pathway

Constitutively active mutations in the Gi2 and GoA subunits of heterotrimeric G proteins have been identified in several human cancers including breast cancer, but their functional significance in tumorigenesis and metastasis has not been well characterized. In this study, we show that expression of the constitutively active GoAR243H and Gi2R179C mutants alone was insufficient to induce mammary tumor formation in mice. However, in transgenic mouse models of breast cancer induced by Neu expression or PTEN loss, we found that the Gi2R179C mutant enhanced spontaneous lung metastasis while having no effect on primary tumor initiation and growth. Additionally, we observed that ectopic expression of the GoAR243H and Gi2R179C mutants in tumor cells promote cell migration in vitro as well as dissemination into multiple organs in vivo by activating c-Src signaling. Thus, our study uncovers a critical function of Gi/o signaling in accelerating breast cancer metastasis via the c-Src pathway. This work is clinically significant, as it can potentially pave the way to personalized therapies for patients who present with active Gi/o mutations or elevated Gi/o signaling by targeting c-Src to inhibit breast cancer metastasis.

cancer biology↗

bioRxiv2021

Targeting Gi/o protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy

G protein coupled receptors (GPCRs) are among the most desirable drug targets for human disease. Although GPCR dysfunction drives the development and progression of many tumors including breast cancer (BC), targeting individual GPCRs has limited efficacy as a cancer therapy because numerous GPCRs are activated. In this study, we sought a new way of blocking GPCR activation in HER2+-BC by targeting a subgroup of GPCRs that couple to Gi/o proteins (Gi/o-GPCRs). Using cell lines and transgenic mouse models, we showed in mammary epithelial cells, HER2 hyperactivation altered GPCR expression, particularly, Gi/o-GPCRs. Gi/o-GPCR stimulation transactivated EGFR and HER2, which in turn activated the PI3K/AKT and Src pathways. Uncoupling Gi/o-GPCRs from cognate Gi/o proteins by pertussis toxin (PTx) inhibited BC cell proliferation and migration in vitro and suppressed HER2-driven tumor formation and metastasis in vivo. Moreover, targeting Gi/o-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that HER2 hyperactivation in BC cells drives aberrant Gi/o-GPCR signaling, and Gi/o-GPCR signals converge on PI3K/AKT and Src signaling pathways to promote cancer progression and the development of resistance to HER2-targeted therapy. Our findings suggest a new way to pharmacologically deactivate GPCR signaling to block tumor growth and enhance therapeutic efficacy.

cancer biology↗

bioRxiv2019

Thinking small: next-generation sensor networks close the size gap in vertebrate biologging

Recent advances in animal tracking technology have ushered in a new era in biologging. However, the considerable size of many sophisticated biologging devices restricts their application to larger animals, while old-fashioned techniques often still represent the state-of-the-art for studying small vertebrates. In industrial applications, low-power wireless sensor networks fulfill requirements similar to those needed to monitor animal behavior at high resolution and at low tag weight. We developed a wireless biologging network (WBN), which enables simultaneous direct proximity sensing, high-resolution tracking, and long-range remote data download at tag weights of one to two grams. Deployments to study wild bats created social networks and flight trajectories of unprecedented quality. Our developments highlight the vast capabilities of WBNs and their potential to close an important gap in biologging: fully automated tracking and proximity sensing of small animals, even in closed habitats, at high spatial and temporal resolution.

animal behavior and cognition↗