Biology subjects

Allam, A. H.

Publications and source records attributed to Allam, A. H..

3 recordsLinked to original sources

bioRxiv2024

Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within Interleukin-6 family cytokines

Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in glandular epithelium of KrasG12D; Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047Ris sufficient to induce adenomas, and that lesions progress to carcinoma when also harboring Pten-deletions. Additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with poorer survival of patients with high IL6 expression, we identify IL6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.

cancer biology↗

bioRxiv2022

E-cadherin in developing murine T cells controls spindle alignment and differentiation during β-selection

A critical stage of T cell development is {beta}-selection; at this stage the TCR{beta} chain is generated and the developing T cell starts to acquire antigenic specificity. Progression through {beta}-selection is assisted by a low affinity interaction between the nascent TCR{beta} chain and peptide presented on stromal MHC and external cues provided by the niche, including Notch and CXCR4. In this study, we reveal the importance of a new cue within the murine developing T cell niche which is critical for T cell development. E-cadherin mediates cell-cell interactions and influences cell fate in many developmental systems. In developing T cells E-cadherin contributed to the formation of an immunological synapse and the alignment of the mitotic spindle with the polarity axis during division, which facilitated subsequent T cell development. Collectively, these data highlight a new aspect of the developing T cell niche and provide insights into the role of E-cadherin in the {beta}-selection stage of T cell development.

cell biology↗

bioRxiv2019

Developing T cells form an immunological synapse for passage through the β-selection checkpoint

The {beta}-selection checkpoint of T cell development tests whether the cell has recombined its genomic DNA to produce a functional T Cell Receptor {beta} (TCR{beta}) receptor. Passage through the {beta}-selection checkpoint requires the nascent TCR{beta} protein to mediate signaling through a pre-TCR complex. In this study, we show that developing T cells at the {beta}-selection checkpoint establish an immunological synapse in in vitro & in situ, resembling that of the mature T cell. The immunological synapse is dependent on two key signaling pathways known to be critical for the transition beyond the {beta}-selection checkpoint, Notch and CXCR4 signaling. In vitro and in situ analyses indicate that the immunological synapse promotes passage through the {beta}-selection checkpoint. Collectively, these data indicate that developing T cells regulate pre-TCR signaling through the formation of an immunological synapse. This signaling platform integrates cues from Notch, CXCR4, and MHC on the thymic stromal cell, to allow transition beyond the {beta}-selection checkpoint.\n\nSummaryT cell development requires testing whether genomic rearrangement has produced a T cell receptor capable of transmitting signals. Most T cells fail this test. Here, we show that passage through the {beta}-selection checkpoint requires assembly of a platform to support TCR signaling.

immunology↗