All Publications
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Correlative studies reveal factors contributing to successful CAR-T cell therapies in cancer.
Cancer metastasis reviews
2024; 44 (1): 15
Abstract
Cellular and targeted immunotherapies have revolutionized cancer treatments in the last several decades. Successful cellular therapies require both effective and durable cytotoxic activity from the immune cells as well as an accessible and susceptible response from targeted cancer cells. Correlative studies from clinical trials as well as real-world data from FDA-approved therapies have revealed invaluable insights about immune cell factors and cancer cell factors that impact rates of response and relapse to cellular therapies. This review focuses on the flagship cellular therapy of engineered chimeric antigen receptor T-cells (CAR-T cells). Within the CAR-T cell compartment, we discuss discoveries about T-cell phenotype, transcriptome, epigenetics, cytokine signaling, and metabolism that inform the cell manufacturing process to produce the most effective and durable CAR-T cells. Within the cancer cell compartment, we discuss mechanisms of resistance and relapse caused by mutations, alternative splicing, post-transcriptional modifications, and cellular reprogramming. Continued correlative and mechanistic studies are required to help us further optimize cellular therapies in a variety of malignancies.
View details for DOI 10.1007/s10555-024-10232-4
View details for PubMedID 39625613
View details for PubMedCentralID 10068450
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AP-1 and TGFSS cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma.
Nature communications
2020; 11 (1): 5079
Abstract
Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFSS cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.
View details for DOI 10.1038/s41467-020-18762-5
View details for PubMedID 33033234
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Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas.
Nature medicine
2018; 24 (3): 271–81
Abstract
Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.
View details for PubMedID 29400712
View details for PubMedCentralID PMC5839965
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G(s)alpha Deficiency in the Ventromedial Hypothalamus Enhances Leptin Sensitivity and Improves Glucose Homeostasis in Mice on a High-Fat Diet
ENDOCRINOLOGY
2016; 157 (2): 600-610
Abstract
In both mice and patients with Albright hereditary osteodystrophy, heterozygous inactivating mutations of Gsα, a ubiquitously expressed G protein that mediates receptor-stimulated intracellular cAMP production, lead to obesity and insulin resistance but only when the mutation is present on the maternal allele. This parent-of-origin effect in mice was shown to be due to Gsα imprinting in one or more brain regions. The ventromedial hypothalamus (VMH) is involved in the regulation of energy and glucose homeostasis, but the role of Gsα in VMH on metabolic regulation is unknown. To examine this, we created VMH-specific Gsα-deficient mice by mating Gsα-floxed mice with SF1-cre mice. Heterozygotes with Gsα mutation on either the maternal or paternal allele had a normal metabolic phenotype, and there was no molecular evidence of Gsα imprinting, indicating that the parent-of-origin metabolic effects associated with Gsα mutations is not due to Gsα deficiency in VMH SF1 neurons. Homozygous VMH Gsα knockout mice (VMHGsKO) showed no changes in body weight on either a regular or high-fat diet. However, glucose metabolism (fasting glucose, glucose tolerance, insulin sensitivity) was significantly improved in male VMHGsKO mice, with the difference more dramatic on the high-fat diet. In addition, male VMHGsKO mice on the high-fat diet showed a greater anorexigenic effect and increased VMH signal transducer and activator of transcription-3 phosphorylation in response to leptin. These results indicate that VMH Gsα/cyclic AMP signaling regulates glucose homeostasis and alters leptin sensitivity in mice, particularly in the setting of excess caloric intake.
View details for DOI 10.1210/en.2015-1700
View details for Web of Science ID 000369965900018
View details for PubMedID 26671183
View details for PubMedCentralID PMC4733121
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Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma.
journal of investigative dermatology
2015; 135 (8): 2138-2141
View details for DOI 10.1038/jid.2015.115
View details for PubMedID 25801792
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Smoothened variants explain the majority of drug resistance in Basal cell carcinoma.
Cancer cell
2015; 27 (3): 342-353
Abstract
Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.
View details for DOI 10.1016/j.ccell.2015.02.002
View details for PubMedID 25759020