Oncology
Abstract
Authors
Rimas V. Lukas, Ruochen Du, Harrshavasan Congivaram, Kathleen McCortney, Karan Dixit, Craig Horbinski, Margaret Schwartz, Raymond Lezon, Lauren Singer, Ditte Primdahl, Jigisha Thakkar, Amy B. Heimberger, Roger Stupp, Priya Kumthekar
Abstract
The survival of patients with acute myelogenous leukemia (AML) carrying mutations in TP53 is dismal. We report the results of a detailed characterization of responses to treatment ex vivo with the MDM2 inhibitor MI219, a p53 protein stabilizer, in AML blasts from 165 patients focusing analyses on TP53 wildtype (WT) patients. In total 33% of AML were absolute resistant to MDM2 inhibitor induced apoptosis, of which 45% carried TP53 mutation and 55% were TP53 WT. We conducted array-based expression profiling of ten resistant and ten sensitive AML cases with WT TP53 status, respectively, at baseline and after 2h and 6h of MDM2 inhibitor treatment. While sensitive cases showed the induction of classical TP53 response genes, this was absent or attenuated in resistant cases. In addition, the sensitive and resistant AML samples at baseline profoundly differed in the expression of inflammation-related and mitochondrial genes. No TP53 mutated AML patient survived. The 4-year survival of AML with defective MDM2 inhibitor induced TP53-mediated apoptosis despite WT TP53 was dismal at 19% when NPM1 was co-mutated and 6% when NPM1 was WT. In summary, we identified prevalent multi-causal defects in TP53-mediated apoptosis in AML resulting in extremely poor patient survival.
Authors
Josephine Dubois, Anthony Palmer, Darren King, Mohamed Rizk, Karan Bedi, Kerby A. Shedden, Sami N. Malek
Abstract
We provide evidence that human and murine SLFN5 proteins are modulators of Type I IFN responses and the immune response in pancreatic cancer. Blocking expression of Slfn5 in PDAC enhances IFN-responses, suppresses tumor growth, and prolongs survival in immunocompetent mice. Notably, immunophenotypic analysis reveals a reduction in tumor-associated macrophages (TAMs) alongside an increase in tumor infiltrating effector cells in tumors over time. These findings implicate SLFN5 acts as an intracellular immune checkpoint and identify it as a unique therapeutic target for the development of therapies for PDAC and possibly other malignancies.
Authors
Mariafausta Fischietti, Markella Zannikou, Elspeth M. Beauchamp, Diana Saleiro, Aneta H. Baran, Briana N. Hryhorysak, Jamie N. Guillen Magaña, Emely Lopez Fajardo, Gavin T. Blyth, Brandyn A. Castro, Jason M. Miska, Catalina Lee-Chang, Priyam Patel, Elizabeth T. Bartom, Masha Kocherginsky, Frank Eckerdt, Leonidas C. Platanias
Abstract
Small cell lung cancer (SCLC) transformation is an incompletely characterized mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant cancers, limiting development of optimal treatment approaches. Through single-cell RNA sequencing of malignant pleural effusions from patients who underwent SCLC transformation, we identified heterogeneity and diversity, including distinct neuroendocrine (NE) and mesenchymal non-NE cancer cell subsets, which were maintained in patient-derived cell lines. We demonstrate that EZH2 regulates EGFR expression in NE cells where EGFR expression is silenced at baseline. Although neither epigenetic derepression nor exogenous overexpression of mutant EGFR sensitized the cells to EGFR inhibition, non-NE cells exhibited selective sensitivity to MEK inhibitors. Combined MEK inhibitor and chemotherapy effectively inhibited growth of both NE and non-NE cells in vitro and in vivo. Our findings demonstrate that EGFR-mutant SCLC is composed of mixed cell states with distinct therapeutic vulnerabilities and offer a therapeutic strategy to target tumor heterogeneity in highly plastic and treatment-resistant malignancies such as transformed SCLC.
Authors
Atsuko Ogino, Amir Vajdi, Xinmeng Jasmine Mu, Navin R. Mahadevan, Kenneth Ngo, Matthew A. Booker, Paloma Cejas, Jeffrey J. Okoro, Man Xu, Benjamin F. Springer, Benjamin K. Eschle, Cameron M. Messier, Stephen Wang, Sudeepa Syamala, Rubii M. Tamen, Anika E. Adeni, Emily S. Chambers, Israel Canadas, Tran Thai, Camilla L. Christensen, Chunxiao Xu, Patrick H. Lizotte, Geoffrey R. Oxnard, Hideo Watanabe, Henry W. Long, Prafulla C. Gokhale, Cloud P. Paweletz, Lynette M. Sholl, Matthew G. Oser, David A. Barbie, Michael Y. Tolstorukov, Pasi A. Jänne
Abstract
Approximately 30% of patients with endometrial carcinomas (ECs) with exon 3 CTNNB1 (β-catenin) mutations experience disease recurrence, whereas others with the same mutations remain recurrence-free. The molecular factors driving mutant β-catenin’s oncogenic and clinical variability are unknown. Here we show that CD73 restrains the oncogenic activity of exon 3 β-catenin mutants, and CD73 loss is associated with recurrence. Using 7 patient-specific β-catenin mutants, together with genetic deletion or ectopic expression of CD73, we demonstrate that CD73 loss increases β-catenin–TCF/LEF transcriptional activity. In CD73-deficient cells, membrane levels of mutant β-catenin decreased, which corresponded with increased levels of nuclear and chromatin-bound mutant β-catenin. These results suggest that CD73 sequesters mutant β-catenin to the membrane to limit its oncogenic activity. Adenosine A1 receptor deletion phenocopied the effects of CD73 loss, implicating adenosine receptor signaling in this regulation. Ectopic CD73 expression suppressed the invasiveness and stemness capacity of β-catenin–mutant EC cells. TCGA analyses, GeoMx digital spatial profiling, and functional analyses showed that CD73 loss drives distinct Wnt–TCF/LEF–dependent gene expression programs linked to cancer cell stemness. These findings identify CD73 as a key regulator of mutant β-catenin, providing mechanistic insight into the variability of recurrence in CTNNB1-mutant EC.
Authors
Rebecca M. Hirsch, Gaith Droby, Sunthoshini Premsankar, Molly L. Parrish, Katherine C. Kurnit, Lilly F. Chiou, Emily M. Rabjohns, Hannah N. Lee, Russell R. Broaddus, Cyrus Vaziri, Jessica L. Bowser
Abstract
Nearly 50% of patients with KRAS-mutant colorectal cancer (CRC) currently lack effective targeted therapy. The accumulation of KRAS-mutant proteins can trigger a sustained high level of endoplasmic reticulum (ER) stress, and the UPR-based long-term protective regulatory pathway inhibits the aggregation of unfolded proteins, thereby maintaining the stability of the ER and enabling the continued survival of KRAS-mutant tumors. However, the critical factors that affect the regulation of ER homeostasis in KRAS-mutant CRC are still unclear. Mono-ADP ribosylation (MARylation) catalyzed by ART1 is the most important modification of GRP78/BiP and stabilizes the internal environment of the ER. In this study, KRAS mutation increased the levels of ART1, ER stress, and MARylated GRP78/BiP in CRC cells. Inhibiting MARylated GRP78/BiP can impede the downstream IRE1α/XBP1/TFAF2/JNK and PERK/eIF2α/ATF4 cascades by affecting the binding and dissociation of GRP78/BiP with receptors to hinder the growth of KRAS-mutant CRC cells and accelerate their apoptosis. We propose that KRAS-mutant CRC cells are more sensitive to intervention with MARylated GRP78/BiP because more modifications are needed to maintain ER stability. We also conducted a preliminary study on the specific site of function. Clarifying this molecular mechanism can provide a experimental basis for identifying effective targets for the intervention of KRAS-mutant CRC.
Authors
Shuxian Zhang, Xiaodan Chen, Qian Gong, Jing Huang, Yi Tang, Ming Xiao, Ming Li, Qingshu Li, Yalan Wang
Abstract
Anoikis resistance or evasion of cell death triggered by matrix detachment is a hallmark of cancer cell survival and metastasis. We show that repeated exposure to suspension stress followed by recovery under attached conditions leads to development of anoikis resistance. The acquisition of anoikis resistance is associated with enhanced invasion, chemoresistance, and immune evasion in vitro and distant metastasis in vivo. This acquired anoikis resistance is not genetic, persisting for a finite duration without detachment stress, but is sensitive to CDK8/19 Mediator kinase inhibition that can also reverse anoikis resistance. Transcriptomic analysis reveals that CDK8/19 kinase inhibition induces bidirectional transcriptional changes in both sensitive and resistant cells, disrupting the balanced reprogramming required for anoikis adaptation and resistance by reversing some resistance associated pathways and enhancing others. Both anoikis resistance and in vivo metastatic growth of ovarian cancers are sensitive to CDK8/19 inhibition, thereby providing a therapeutic opportunity to both prevent and suppress ovarian cancer metastasis.
Authors
Mehri Monavarian, Resha Rajkarnikar, Emily Faith Page, Asha Kumari, Liz Quintero Macias, Felipe Massicano, Nam Y. Lee, Sarthak Sahoo, Nadine Hempel, Mohit Kumar Jolly, Lara Ianov, Elizabeth Worthey, Abhyudai Singh, Igor B. Roninson, Eugenia V. Broude, Mengqian Chen, Karthikeyan Mythreye
Abstract
Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts (myCAFs) that are intimately associated with invasive tumor cells and correlate with poor prognosis, lymph node metastasis, and disease progression in thyroid carcinoma. We also revealed a population of inflammatory CAFs that are distant to tumor cells and are found in the inflammatory stromal microenvironment of autoimmune thyroiditis. Together, our study provides spatial profiling of thyroid cancer evolution in samples with mixed WDTC/ATC histopathology and identifies a prognostic myCAF subtype with potential clinical utility in predicting aggressive disease in both children and adults.
Authors
Matthew A. Loberg, George J. Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C. Wahoski, Kailey P. Caroland, Megan L. Tigue, Heather A. Hartmann, Jean-Nicolas Gallant, Courtney J. Phifer, Andres A. Ocampo, Dayle K. Wang, Reilly G. Fankhauser, Kirti A. Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M. Shaddy, James L. Netterville, Sarah L. Rohde, Carmen C. Solórzano, Lindsay A. Bischoff, Naira Baregamian, Barbara A. Murphy, Jennifer H. Choe, Jennifer R. Wang, Eric C. Huang, Quanhu Sheng, Luciane T. Kagohara, Elizabeth M. Jaffee, Ryan H. Belcher, Ken S. Lau, Fei Ye, Ethan Lee, Vivian L. Weiss
Abstract
Radiotherapy is a critical modality in cancer treatment, not only to eradicate cancer cells but also to trigger anti-tumor immunity. Interleukin-21 (IL-21), an immunomodulatory cytokine with potential in cancer therapy, has unexplored synergy with radiotherapy. Our study, leveraging human cancer databases and tissue microarrays, identified a positive correlation between IL-21 and radiotherapy outcomes, particularly in tumor microenvironment (TME) activation. In mouse tumor models, IL-21 combined with radiation significantly enhances TME, boosting CD8+ T cell activation and function, reducing tumor burden, and extending survival. Single-cell transcriptome sequencing revealed that the combination of IL-21 and radiation increased the cytotoxicity of effector and memory CD8+ T cells and prevented their exhaustion. These effects were further validated in humanized mice, where IL-21 combined with radiation reduced A549 tumor growth and enhanced CD8+ T cell function. Post-neoadjuvant radiotherapy samples from patients with esophageal cancer showed a positive correlation between IL-21 levels and CD8+ T cell infiltration. Our findings suggest that IL-21 is a promising adjuvant to radiotherapy, potentially improving the treatment efficacy through TME enhancement. This study provides a foundation for future clinical exploration of IL-21 for enhancing radiotherapy.
Authors
Xinyang Li, Xueqi Xie, Baochao Wei, Xiaozheng Sun, Minxin Chen, Rufei Liu, Qingxu Tao, Yiheng Huang, Qian Wang, Shuangshuang Ma, Ling Wei, Rong Xiao, Zhaoyun Liu, Jinming Yu, Meng Wu, Dawei Chen
Abstract
The tumor microenvironment plays a key role in cancer progression and therapy resistance, with cancer-associated fibroblasts (CAFs) contributing to desmoplasia, extracellular matrix (ECM) remodeling, and elevated interstitial fluid pressure, all of which hinder drug delivery. We investigated fibroblast activation protein–targeted (FAP-targeted) near-infrared photoimmunotherapy (NIR-PIT) as a strategy to improve drug penetration in CAF-rich tumors. In clinical esophageal cancer samples, FAP expression strongly correlated with increased collagen I, hyaluronic acid, and microvascular collapse. CAF-rich 3D spheroids demonstrated elevated ECM deposition and significantly impaired drug uptake compared with CAF-poor models. FAP-targeted NIR-PIT selectively reduced CAFs, reduced ECM components, and restored drug permeability. In vivo, FAP-targeted NIR-PIT enhanced the accumulation of panitumumab and Abraxane in CAF-rich tumors and improved antitumor efficacy when combined with chemotherapy. These findings highlight FAP-targeted NIR-PIT as a promising therapeutic approach to remodel the tumor stroma and overcome drug resistance in desmoplastic solid tumors.
Authors
Seitaro Nishimura, Kazuhiro Noma, Tasuku Matsumoto, Yasushige Takeda, Tatsuya Takahashi, Hijiri Matsumoto, Kento Kawasaki, Hotaka Kawai, Tomoyoshi Kunitomo, Masaaki Akai, Teruki Kobayashi, Noriyuki Nishiwaki, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Shunsuke Tanabe, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Peter L. Choyke, Hisataka Kobayashi, Toshiyoshi Fujiwara
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