Biology subjects

Hansson, J.

Publications and source records attributed to Hansson, J..

6 recordsLinked to original sources

bioRxiv2026

Structural survey of HIF-2α reveals regulation of its subcellular localization and protein interactome

Hypoxia-inducible factor 2 (HIF-2) is a central regulator of cellular homeostasis and a known oncogenic driver in multiple cancers. Although HIF-2 is canonically defined as a nuclear transcription factor, its cytoplasmic presence and non-canonical functions remain poorly understood. Here, we performed a structural survey of HIF-2 to determine the mechanisms underlying subcellular localization, protein abundance, and activity using a deletion-construct library, transcriptional assays, and in vivo xenograft models. We found that the oxygen-dependent degradation domain (ODD), the N-terminal intrinsically disordered region (n-IDR) and the N-terminal transactivation domain (NTAD) promote cytoplasmic localization, whereas the C-terminal IDR drives nuclear accumulation. Surprisingly, we found that HIF-2 nuclear localization occurs also in the absence of PAS A and B, the domains required for ARNT (HIF-1{beta}) dimerization, resolving the long-standing question in the field. These data suggest a dominant role for non-canonical cytoplasmic mechanisms in HIF-2-driven tumorigenesis. Strikingly, neither NTAD nor the C-terminal CTAD was required for tumor growth in vivo, in coherence with our transcriptional assays indicating that CTAD is dispensable for transactivation and NTAD functions as a suppressor rather than an activator of transcription. Proteomic analyses reveal HIF-2 interactions with regulators of mitochondrial function, translation initiation, RNA splicing, vesicular transport, and DNA replication. Together, these findings uncover previously unrecognized structural and functional complexity of HIF-2 compartmentalization and expand its role beyond canonical transcriptional regulation.

cell biology↗

bioRxiv2026

Cancer-associated KBTBD4 mutations induce differentiation defects and confer a unique therapeutic vulnerability

Epigenetic regulation governs stem cell fate and perturbations in these mechanisms often lead to tumor development. The CoREST complex, a critical regulator of neural and hematopoietic stem cell differentiation, is recurrently targeted by gain of function mutations in the ubiquitin ligase KBTBD4 in high-risk embryonal brain tumors. However, the tumorigenic potential of these mutations remains unresolved partly due to the challenges in modelling tumors that arise during early brain development. We and others recently demonstrated that small molecule UM171 mimics KBTBD4 mutations by promoting robust CoREST degradation and expansion of hematopoietic stem cells. Leveraging this mechanistic similarity, we modeled KBTBD4 mutations in hematopoietic stem and progenitor cells (HSPCs) and found that mutants induced expansion of immature stem and progenitor populations and impaired lineage differentiation. High-throughput screening identified HDAC inhibitors as specific agents that disrupt mutant KBTBD4 activity, by preventing interaction with the CoREST complex. Using our HSPC model, we demonstrated that the class I HDAC inhibitor mocetinostat alleviated differentiation defects caused by KBTBD4 mutations. Together, these findings reveal the tumorigenic mechanism of KBTBD4 mutations and uncover therapeutic vulnerabilities that may be exploited for clinical applications.

cancer biology↗

bioRxiv2025

Palbociclib CDK4/6- and Crizotinib MET/ALK/ROS1-inhibitors Synergize to Enhance Senescence and Immune Recognition in Melanoma Cells Independently of BRAF/NRAS Status

"Pro-senescence therapy", which triggers both permanent cell cycle arrest and an immune response, has been proposed as a strategy for cancer treatment, but is still controversial. To assess this strategy in melanoma, we performed a high throughput microscopy-based senescence screen utilizing a panel of melanoma cell lines with different driver mutations and a collection of clinical and experimental drugs. We found that vemurafenib and trametinib, which inhibit BRAFV600E and MEK1/2, respectively, induced senescence in some but not all BRAF-mutant cell lines. In contrast, palbociclib, BKM-120 and crizotinib, which inhibit CDK4/6, PI3K, and MET/ALK/ROS1, respectively, triggered senescence in most cell lines, irrespective of BRAF/NRAS mutation status, and overcame intrinsic and acquired vemurafenib resistance. The combination of palbociclib and crizotinib synergized to further enhance the senescence response in all cell lines irrespective of BRAF/NRAS mutation status, increased the expression of SASP factors, such as IL-1 and {beta}, and HLA class I and other markers for recognition by NK and T cells. Further, this combination caused a significant increase in CD8+ T cells and pro-inflammatory macrophages in the tumor microenvironment and a marked reduction of mouse melanoma tumor growth that was dependent on CD8+ T cells, suggesting increased immune surveillance. Our findings suggest that pro-senescence therapy based on concomitant inhibition of both CDK4/6 and MET/ALK/ROS1 could be developed further as an alternative treatment strategy for melanoma. Significance: Pro-senescence therapy based on combined targeting of CDK4/6 with palbociclib and MET/ALK/ROS1 with crizotinib inhibits melanoma tumor growth through anti-tumor immune response activation, providing an alternative treatment strategy for melanoma.

cancer biology↗

bioRxiv2023

Defective ribosome assembly impairs leukemia stem cell function in a murine model of acute myeloid leukemia

Despite the advanced understanding of disease mechanisms, the current therapeutic regimen fails to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of protein synthesis control in AML leukemia stem cell (LSC) function and leukemia propagation. We apply a murine model of mixed-lineage leukemia-rearranged AML to demonstrate that LSCs are characterized by high global protein synthesis rate. Using a genetic model that permits inducible and graded regulation of ribosomal subunit joining, we show that defective ribosome assembly leads to a significant survival advantage by selectively eradicating LSCs but not normal hematopoietic stem and progenitor cells. Finally, transcriptomic and proteomic analyses identify a rare subset of LSCs with immature stem cell signature and high ribosome content that promotes the resistance to defective ribosome assembly. Collectively, our study unveils a critical requirement of high protein synthesis rate for LSC function and highlights ribosome assembly as a therapeutic target in AML.

cancer biology↗

bioRxiv2021

Identification of cardiac afterload dynamics from data

The prospect of ex vivo functional evaluation of donor hearts is considered. Particularly, the dynamics of a synthetic cardiac afterload model are compared to those of normal physiology. A method for identification of continuous-time transfer functions from sampled data is developed and verified against results from the literature. The method relies on exact gradients and Hessians obtained through automatic differentiation. This also enables straightforward sensitivity analyses. Such analyses reveal that the 4-element Windkessel model is not practically identifiable from representative data while the 3-element model underfits the data. Pressure-volume (PV) loops are therefore suggested as an alternative for comparing afterload dynamics.

bioengineering↗

bioRxiv2020

PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma

Approximately 50% of human cutaneous melanomas carry activating mutations in the serine/threonine protein kinase BRAF. BRAF inhibitors (BRAFi) selectively target the oncogenic BRAFV600E/K and are effective in approximately 80% of patients carrying the mutation. However, resistance to BRAFi is common and emerges within a median time of 6-7 months of treatment and is prolonged to 11 months when combined with MEK inhibitors. Better characterization of the underlying molecular processes is therefore needed to further improve treatments. Inactivation of the tumor suppressor gene PTEN has been suggested to occur during melanomagenesis and drug resistance development. We recently demonstrated that transcription of PTEN is negatively regulated by an antisense RNA from the PTEN pseudogene (PTENP1-AS) and here set out to investigate the impact of this molecular pathway on the resistance to BRAFi and clinical outcome. We used a panel of BRAFi resistant A375 sublines, and observed increased levels of PTENP1-AS associated with reduced expression of PTEN. Furthermore, this loss of PTEN expression was correlated to increased recruitment of Enhancer of zeste homolog 2 (EZH2) and formation of the transcriptional repression mark H3K27me3 at the PTEN promoter in the resistant cells. We demonstrated that targeting of PTENP1-AS was able to re-activate the expression of PTEN and sensitize resistant melanoma cells to BRAFi. Finally, we showed that PTENP1-AS is a promising prognostic marker for clinical outcome in melanoma patients as high expression of PTENP1-AS in regional lymph node metastases from stage III melanoma patients correlated with poor survival.

cancer biology↗