Biology subjects

Sarin, K. Y.

Publications and source records attributed to Sarin, K. Y..

3 recordsLinked to original sources

bioRxiv2025

Dissection of Gαs and Hedgehog signaling crosstalk reveals therapeutic opportunities to target adenosine receptor 2b in Hedgehog-dependent tumors

Basal cell carcinoma (BCC), the most common human cancer, is driven by hyperactivation of Hedgehog Smoothened (SMO) and GLI transcription. Gs and protein kinase A (PKA) negatively regulate Hedgehog signaling, offering an alternative BCC development and treatment pathway. Here, using histology alongside bulk and single-cell RNA sequencing, we find that mouse BCC-like tumors that originate from Gs pathway inactivation are strikingly similar to those driven by canonical Hedgehog SMO. Interestingly, mutations that reduce Gs and PKA activity are present in human BCC. Tumors from Gs pathway inactivation are independent of the canonical Hedgehog regulators SMO and GPR161, establishing them as an SMO-independent oncogenic Hedgehog signaling model. Finally, we demonstrate that activation of the Gs-coupled adenosine 2B receptor counteracts oncogenic SMO, reducing Hedgehog signaling and tumor formation and offering a potential therapeutic strategy for BCC.

cancer biology↗

bioRxiv2021

ERK2 MAP kinase regulates SUFU binding by multisite phosphorylation of GLI1

There is considerable evidence that crosstalk between the Hedgehog and MAPK signaling pathways occurs in several types of cancer, and contributes to the emergence of clinical resistance to Hedgehog pathway inhibitors. Here we show that MAP kinase-mediated phosphorylation weakens the binding of the GLI1 transcription factor to its negative regulator SUFU. ERK2 phosphorylates GLI1 on three evolutionarily-conserved target sites (S102, S116 and S130) located near the high-affinity binding site for SUFU; these phosphorylations cooperate to weaken the affinity of GLI1-SUFU binding by over 25 fold. Phosphorylation of any one, or even any two, of the three sites does not result in the level of SUFU release seen when all three sites are phosphorylated. Tumor-derived mutations in R100 and S105, residues bordering S102, also diminish SUFU binding, collectively defining a novel evolutionarily-conserved SUFU-affinity-modulating region. In cultured mammalian cells, GLI1 variants containing phosphomimetic substitutions of S102, S116 and S130 displayed an increased ability to drive transcription. We conclude that of multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk.

cell biology↗

bioRxiv2019

Clonal replacement of tumor-specific T cells following PD-1 blockade

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, which tumor-specific T cells are mobilized following checkpoint blockade remains unclear. Here, we performed paired single-cell RNA- and T cell receptor (TCR)-sequencing on 79,046 cells from site-matched tumors from patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) pre- and post-anti-PD-1 therapy. Tracking TCR clones and transcriptional phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the T cell response to treatment was accompanied by clonal expansions of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this expansion did not derive from pre-existing tumor infiltrating T cell clones; rather, it comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells, compared to other distinct T cell phenotypes, and was evident in BCC and SCC patients. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that pre-existing tumor-specific T cells may be limited in their capacity for re-invigoration, and that the T cell response to checkpoint blockade relies on the expansion of a distinct repertoire of T cell clones that may have just recently entered the tumor.

immunology↗