Biology subjects

Rosel, D.

Publications and source records attributed to Rosel, D..

4 recordsLinked to original sources

bioRxiv2024

Migrastatic Therapy as a Potential Game-Changer inAdaptive Cancer Treatment

Adaptive therapy, which anticipates and counters the evolution of resistance in cancer cells, has gained significant traction, especially following the success of the Zhang et al.s protocol in treating metastatic castrate-resistant prostate cancer. While several adaptive therapies have now advanced to clinical trials, none currently incorporates migrastatics, i.e. treatments designed to inhibit cancer cell metastasis. In this study, we propose integrating migrastatics into adaptive therapy protocols and evaluate the potential benefits of using a game-theoretic spatial model. Our results demonstrate that combining adaptive therapy with migrastatics effectively delays the onset of metastasis and reduces both the number and size of metastases across most cancer scenarios analyzed. This approach not only extends the time to the first metastasis but also enhances the overall efficacy of adaptive therapies. Our findings suggest a promising new direction for cancer treatment, where adaptive therapy, in combination with migrastatic agents, can target both the evolution of resistance and the metastatic spread of cancer cells.

cancer biology↗

bioRxiv2024

Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis.

The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/AKT signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.

cancer biology↗

bioRxiv2022

Phosphorylation of tyrosine 90 in SH3 domain is a new regulatory switch controlling Src kinase

The activation of Src kinase in cells is strictly controlled by intramolecular inhibitory interactions mediated by SH3 and SH2 domains. They impose structural constraints on the kinase domain holding it in a catalytically non-permissive state. The transition between inactive and active conformation is known to be largely regulated by the phosphorylation state of key tyrosines 416 and 527. Here we identified that phosphorylation of tyrosine 90 reduces binding affinity of the SH3 domain to its interacting partners, opens the Src structure, and renders Src catalytically active. This is accompanied by an increased affinity to the plasma membrane, decreased membrane motility and slower diffusion from focal adhesions. Phosphorylation of tyrosine 90 controlling SH3-medited intramolecular inhibitory interaction, analogical to tyrosine 527 regulating SH2-C-terminus bond, enables SH3 and SH2 domains to serve as cooperative but independent regulatory elements. This mechanism allows Src to adopt several distinct conformations of varying catalytic activities and interacting properties, enabling it to operate not as a simple switch but as a tunable regulator functioning as a signaling hub in a variety of cellular processes.

cell biology↗

bioRxiv2018

The interaction of p130Cas with PKN3 promotes malignant growth

Protein p130Cas constitutes an adaptor protein mainly involved in integrin signaling downstream of Src kinase. Owing to its modular structure, p130Cas acts as a general regulator of cancer cell growth and invasiveness induced by different oncogenes. However, other mechanisms of p130Cas signaling leading to malignant progression are poorly understood. Here, we show a novel interaction of p130Cas with Ser/Thr kinase PKN3, which is implicated in prostate and breast cancer growth downstream of phosphoinositide 3-kinase. This direct interaction is mediated by the p130Cas SH3 domain and the centrally located PKN3 polyproline sequence. PKN3 is the first identified Ser/Thr kinase to bind and phosphorylate p130Cas and to colocalize with p130Cas in cell structures that have a pro-invasive function. Moreover, the PKN3-p130Cas interaction is important for mouse embryonic fibroblast growth and invasiveness independent of Src transformation, indicating a distinct mechanism from that previously characterized for p130Cas. Together, our results suggest that the PKN3-p130Cas complex may represent an attractive therapeutic target in late-stage malignancies.\n\nSummaryGemperle et al. present the first report of an interaction between p130Cas with the serine/threonine kinase PKN3, implicated in prostate and breast cancer growth. They show that p130Cas colocalizes with PKN3 in cell structures that have a pro-invasive function and enhance our understanding of PKN3-mediated signaling and tumor growth.

cancer biology↗