- by Woo, B. J., Sobti, S., Suh, J. M., Yousefi, H., Garcia, K., Zhou, S., Borah, A., Goodarzi, H.Intratumoral transcriptional heterogeneity (ITH) enables tumor cells to explore diverse phenotypic states, fueling therapeutic resistance and metastatic progression. Yet systematic approaches for identifying non-genetic regulators of this phenotype have been lacking. Here, we develop a multi-scale screening framework that integrates bulk patient transcriptomics, functional in vivo genetic screening, and single-cell transcriptomic and epigenomic profiling to nominate chromatin organizers that modulate ITH in breast cancer. From an initial set of 41 candidates nominated in silico, we identify RNF8 and MIS18A as […]
- by Wold, E., Merrill, N. M., Serhan, H., Udager, A., Liu, C. J., Gu, N., Bao, L., Qin, Z., Heth, J., Soellner, M., Merajver, S. D., Morikawa, A.Patient-derived organoids from breast cancer brain metastases enable real-time drug sensitivity testing integrated with genomic profiling. Drug response varied by subtype and molecular alterations. PI3K inhibitors showed activity regardless of PIK3CA mutation status. Pronounced tumor heterogeneity highlighted the urgent need for effective therapies personalized for each patient. Functional assays and molecular matching can help tailor therapy for patients who need the most effective next treatment quickly and warrant further translational evaluation to address this unmet need.
- by Wang, Y., Reshetnikova, E., Katuwal, N. B., Bharti, V., Pereira, M. S., Oppong, B. A., Lee, D. A., Mittra, A., Freud, A. G., Vilgelm, A. E.CDK4/6 inhibitors are standard-of-care for metastatic estrogen receptor-positive (ER+) breast cancer, yet the development of resistance remains a significant clinical hurdle. While CDK4/6 inhibitors are primarily recognized for their ability to induce cytostasis, their role in modulating innate immune responses remains poorly defined. Here, we demonstrated that CDK4/6i treatment remodels the tumor cell surface to favor recognition and elimination by Natural Killer (NK) cells. Using a diverse biobank of patient-derived organoids (PDOs), we found that CDK4/6 inhibition robustly upregulated the […]
- by Nazir, A., Wang, H., Lu, Z., Lau, J., Peale, F., Jesudason, R., Connolly, K. A., Andrusivova, Z., Lau, J., Gierke, S., Peng, L., Chan, S., Jiang, J., Rost, S., Lubeck, E., Simone, M. D., Daniel, B., McGinnis, L. M., Maddalo, D., Joshi, N. S., Garraway, L. A., Regev, A.Prostate cancer (PCa) is a lethal malignancy that displays profound resistance to immune checkpoint blockade (ICB), via mechanisms that are poorly understood. Here, we investigate the causes of CD8 T cell exhaustion and mechanisms of tumor progression in a PCa animal model, by single cell and spatial profiling, along a time course, following orthotopic transplantation of RB1/TP53/PTEN-deficient mouse organoids, competent to express neoantigens. The resulting tumors were castration resistant, consisting of largely basal and L2 malignant cells with upregulated inflammatory […]
- by Dehghan Manshadi, M., Panchal, N. K., Sun, L.-Z., Setoodeh, P., Zare, H.Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Current treatments offer limited efficacy and no definitive cure, underscoring the urgent need for more selective and effective therapeutic strategies. This study investigated the synthetic lethality caused by co-targeting two metabolic genes, ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH), in HCC cells. Using valproic acid (VPA) and bempedoic acid (BA) as pharmacological inhibitors of OGDH and ACLY, respectively, we observed a strong synergistic effect in inhibiting the proliferation […]
- by Fu, R., Wang, Y., Rehman, I., Bedford, E., Sharif, S., Nguyen, N. D., Powell, R. T., Adams, A., Liu, W., Wang, S., He, W., Lu, Y., Liu, B., Shah, P. A., Rodon Ahnert, J., Chen, T., Peng, W., Stephan, C. C., Liu, X., Bedford, M. T., Xu, H.Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine phosphorylase-deleted (MTAP-null) cancers. Second-generation MTA-cooperative PRMT5 inhibitors preferentially target MTAP-null cells while largely sparing MTAP-wildtype (MTAP-WT) cells, thereby improving tumor selectivity over first-generation PRMT5 inhibitors. Despite encouraging efficacy and safety signals in early clinical studies, the modest objective response rates (ORRs) observed with these inhibitors suggest that intrinsic or acquired resistance may limit their clinical benefit. Here, we investigated mechanisms of acquired resistance to the MTA-cooperative PRMT5 inhibitor […]
- by Novoa Diaz, M. B., Carriere, P. M., Birkenstok, C., Gonzalez Osorio, S., Zwenger, A., Contreras, H., Gentili, C.In the tumor microenvironment (TME), dynamic interactions between cells and soluble factors promote tumor progression. We previously demonstrated that parathyroid hormone-related peptide (PTHrP), a TME-associated cytokine, enhances the aggressive phenotype of HCT116 colorectal cancer (CRC) cells, and that conditioned medium from PTHrP-treated HMEC-1 endothelial stromal cells (CM) induces epithelial-to-mesenchymal transition (EMT) in CRC cells. Here, Western blot analysis showed that CM modulates Met receptor expression and activation and promotes cancer stem cell (CSC) traits in HCT116 cells. Since PTHrP induces […]
- Transcriptomic subtypes in high-grade serous ovarian cancer are driven by tumor cellular compositionby Tanis, S., Lixandrao, M., Ivich, A., Grieshober, L., Lawson-Michod, K. A., Collin, L. J., Peres, L. C., Salas, L. A., Marks, J. R., Bitler, B. G., Greene, C. S., Schildkraut, J. M., Doherty, J. A., Davidson, N. R.High-grade serous ovarian carcinoma (HGSC) is an aggressive malignancy for which bulk transcriptomic subtypes are used to stratify tumors, interpret biology, and guide biomarker development. The four TCGA-derived subtypes, mesenchymal (C1.MES), immunoreactive (C2.IMM), proliferative (C5.PRO), and differentiated (C4.DIF), are consistently observed across cohorts. However, despite their prominence, these subtypes have not translated into therapeutic utility, and their biological basis remains unresolved. Here, we show that HGSC transcriptomic subtypes are largely determined by tumor cellular composition rather than intrinsic malignant transcriptional […]
- by Diehl, J., Scuoppo, C., Ramirez, R., Koester, M., Leong, S., Mattes, Z. F., Gallagher, E., Lee, B., Abbate, F., Ghamsari, L., Merutka, G., Vainstein-Haras, A., Kappel, B. J., Rotolo, J. A.Glioblastoma (GBM) is the most prevalent primary brain cancer, with poor prognosis and limited therapeutic options available. The genetic and cellular heterogeneity characteristic of GBM contributes to poor response rates. Activating mutations of the epidermal growth factor receptor (EGFR) gene are among the most frequent alterations in GBM, occurring in roughly half of cases. Despite the prevalence of EGFR mutations, EGFR inhibition has shown limited success in GBM. The transcription factor C/EBP{beta} is a master regulator of the mesenchymal transformation […]
- by Lee, S., Husmann, A., Li, J., Li, C. Z., Modi, S., Ahmad, S., Mackay, S., Paul, A., Jackson, M. R., Chalmers, A. J., McCarthy, N., Gomez-Roman, N. J., Bello, E.Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Radioresistance, partly mediated by glioma stem-like cells, represents a major clinical challenge which could be overcome by the identification of the modulators of radioresistance. Existing CRISPR screens in human GBM models have largely used two-dimensional cultures with short-term viability readouts, failing to capture the long-term clonogenic behaviour underlying tumour recurrence after radiotherapy. Method: We developed ClonoScreen3D-CRISPRi, combining CRISPRi-mediated gene knockdown with three-dimensional clonogenic survival assays. Two GBM cell […]
- by Ota, K., Ito, T., Shimizu, H.A substantial proportion of cancer patients fail to benefit from their prescribed combination regimens, yet identifying superior alternatives from the vast pharmacological space prior to treatment failure remains an unsolved clinical challenge. Existing computational approaches either rely on multi-omics profiles unavailable in standard oncological practice or reduce drug efficacy to scalar metrics that discard the dose-dependent resolution essential for therapeutic optimization. Here, we present XACT, a hierarchical deep learning framework that reconstructs full dose-dependent drug responses for both monotherapy and […]
- by Marzban, S., Robertson-Tessi, M., West, J.Mechanistic modeling has long been used as a tool to describe the dynamics of biological systems, especially cancer in response to treatment. Their key advantage lies in interpretability of relationships between input parameters and outcomes of interest. In contrast, machine learning techniques offer strong prediction performance, especially for high dimensional datasets that are common in oncology. Here, we employ a Mechanstic Learning framework that combines the advantages of both approaches by training machine learning models on mechanistic parameters inferred from […]
- by Velazquez Quesada, I., Belova, E., Jarrah, A., Cesar Mariano, M. C., Dahleh, Y., de Assis Lima, M., Barbosa Vendramini Costa, D., Francescone, R., Cukierman, E., Hodgson, L., Gligorijevic, B.Breast cancer is globally the most common cancer among women. Although the five-year survival rate exceeds 80% for patients with localized disease, it drops to approximately 30% once metastasis occurs, underscoring the urgent need to define mechanisms that drive metastatic progression. Breast is a highly innervated organ and most of its innervation is sensory. However, whether sensory neurons can directly impact breast cancer cells remains an understudied topic. Here, we show that mammary tumors have increased CGRP+ sensory innervation. Using […]
- by Pizzagalli, M., Sasipalli, S., Leary, O., Tran, L., Haas, B., Tapinos, N.Background: Transposable elements (TEs) account for over half of the human genome and are often derepressed in cancer. TEs can add cryptic splice sites, undergo exonization, and generate gene-TE fusion transcripts, but the combined effects of TEs on RNA processing and translation in glioblastoma stem cells (GSCs) remains incompletely elucidated. Results: We combined long-read RNA sequencing with polysome profiling in four patient-derived GSCs and two neural stem cell (NSC) controls to resolve TE-associated transcript diversity and its relationship to ribosomal […]
- by Chakraborty, R., Shah, R., Chien, A., Akter, M., Amirkhani, A., Winn, T., Shen, C., Shahbazi, M.-A., Tukova, A., Shannon, K.Adenoid cystic carcinoma (ACC) of salivary gland is an immune-cold tumour. Annexin A3 (ANXA3) is an apoptotic protein found to be participating in immune cell infiltration in tumour microenvironment (TME) of various cancer cases. Significant low expressions of ANXA3 protein found in adenoid cystic carcinoma. We hypothesized overexpressing ANXA3 transforms ACC cold TME to hot. We cultured UM-HACC-2A and UFH2 spheroids on extracellular matrix and co cultured them with peripheral blood mononuclear cells. We functionalized FDA (The Food and Drug […]
- by Chang, W.-H., Vaughan, A. J., Stamey, A. G., Mancini, M., Hayashi, M., Yang, R., Robb, R., Andrussier, D., Klomp, J. A., Waters, A. M., Schaefer, A., Wolpin, B. M., Bryant, K. L., Cox, A. D., Simabuco, F. M., Wong, K.-K., Aguirre, A. J., Stalnecker, C. A., Papagiannakopoulos, T., Der, C. J.The recent approval of KRAS inhibitors supports the therapeutic value of targeting mutant KRAS cancers. However, clinical efficacy is hindered by both primary and treatment-associated acquired resistance. We applied a CRISPR-Cas9 loss-of-function screen and identified loss of KEAP1 as a resistance mechanism to the KRASG12D-selective inhibitor MRTX1133 and the RAS(ON) multi-selective inhibitor RMC-7977 in pancreatic cancer models. RNA-sequencing analyses revealed a KEAP1KO transcriptome that is distinct from the ERK-, MYC-, and YAP/TAZ-TEAD-dependent transcriptional programs that drive KRAS inhibitor resistance, demonstrating […]
- by Wang, X., Sisoudiya, S., Bihie, M., Greatti, Y., Grandvallet Contreras, J., Jun, T., Sivakumar, S., Huang, K.-l.Germline pathogenic variants in BRCA1 and BRCA2 confer disproportionately elevated cancer risks in breast and ovarian tissues, yet the basis for this tissue specificity remains incompletely understood. Here, we integrate bulk-tumor aneuploidy analysis across 340,824 cancer cases from three independent cohorts (TCGA, ICGC PCAWG, and FoundationCore) with single-cell whole-genome sequencing from two independent studies to investigate whether tissue-specific patterns of chromosomal deletion contribute to this phenomenon. We find that breast and ovarian cancers are consistently enriched for deletions of chromosome […]
- by Danese, N. A., Kurkcu, S. R., Bleiler, M., Nito, K., Kuo, A., Rosenberg, D. W., Nakanishi, M., Giardina, C.Increased matrix metalloproteinase (MMP) expression has long been recognized as a common feature of colorectal cancers (CRCs), yet less is known about how these enzymes interact to impact cancer progression. Taking advantage of single-cell and spatial transcriptomic data, we analyzed the cell-type-specific and spatial expression of MMPs in CRCs. Distinct colon cancer-associated fibroblast (CAF) subtypes were found to express di[erent MMP combinations, including MMP1/3-expressing and MMP11-expressing CAFs. Conversely, myeloid cells (monocytes, macrophages, and dendritic cells) expressed varying levels of the […]
- by Bakhoum, S. F., Bowler, T., Andreu, C., Arora, A., Chen, S., Vedula, C., Roopnariane, A., Bettigole, S., Bosco, N., Dohadwala, A., The SOVI-2302 Investigators,, The VLS-1488-2201 Investigators,, Southwell, D., Ganem, N.KIF18A inhibition has emerged as a therapeutic strategy for chromosomally unstable cancers, but clinical development is limited by the absence of a deployable predictive biomarker. Here we identify strong, diffuse p16INK4a expression, a well-established surrogate marker of Rb-pathway inactivation, as a predictive biomarker of response to KIF18A inhibition, and show that Rb-pathway inactivation marks a biologically distinct subset of cancers sensitive to this therapeutic approach. In sensitive models, low Rb activity is associated with robust spindle assembly checkpoint signaling and […]
- by Wolf, C. L., Ruiz, R. K., Khou, S., Cornelison, R., Stelow, E. B., Kowalewski, K. M., Lazzara, M. J., Poissonnier, A., Coussens, L. M., Kelly, K. A.Background: Pancreatic adenocarcinoma (PDAC) is an abysmal disease, with a poor clinical outcome, largely due to limited life-extending treatments for patients. Notoriously, PDAC displays a T cell-suppressive tumor microenvironment where underlying molecular mechanisms that lead to this phenotype remain poorly understood. To unravel specific mechanisms, we utilized bioinformatic analyses with functional studies and revealed the cytolinker protein plectin (PLEC) as a novel player in regulating the T cell-suppressive tumor microenvironment of PDAC. Methods: Utilizing the TCGA-PAAD dataset, tumor samples were […]
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