Oncology
Abstract
Acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) limits their therapeutic benefits in patients with high-grade serous ovarian cancer (HGSC). Identifying therapeutic vulnerabilities that function across distinct forms of acquired PARPi resistance is an urgent need. In BRCA2-deficient PARPi-naive cells, targeting RAD52 can be synthetic lethal with a PARPi, making RAD52 an attractive therapeutic target. However, this approach has not been tested in HGSC models of acquired PARPi resistance. Here, we assessed the effects of RAD52 loss in 2 distinct Brca2-deficient mouse models of HGSC with acquired PARPi resistance. RAD52 loss suppressed homologous recombination and single-strand annealing DNA repair activity in both models. Genetic depletion and pharmacologic inhibition of RAD52 restored PARPi sensitivity both in vitro and in vivo. Furthermore, RAD52 expression was elevated in a newly derived human model of BRCA2-deficient HGSC with acquired PARPi resistance. In this cell line, RAD52 inhibition synergized with a PARPi. Finally, elevated RAD52 expression was associated with poor survival in patients with HGSC. Collectively, these findings establish RAD52 as a clinically relevant therapeutic vulnerability in multiple models of HGSC with acquired PARPi resistance.
Authors
Yukihide Ota, Maia L. Elizagaray, Vijayalaxmi Gupta, Bisiayo E. Fashemi, Moreniola Akande, Preedia Babu, Prasanth Kumar Thuthika, Elena Lomonosova, Joshua Brill, Lulu Sun, Brooke Sanders, Lindsay M. Kuroki, Carolyn K. McCourt, Andrea R. Hagemann, Ian S. Hagemann, Premal H. Thaker, David G. Mutch, Matthew A. Powell, Krzysztof Hyrc, Priyanka Verma, John Krais, Benjamin G. Bitler, Mary M. Mullen, Dineo Khabele
Abstract
Cancer cachexia is a debilitating syndrome of involuntary body mass loss featuring profound skeletal muscle wasting and high mortality. Cardiac muscle wasting is prominent in cancer patients and cancer survivors. We developed a human induced pluripotent stem cell–derived cardiac myocyte (hiPSC-CM) platform modeling cancer cachexia using conditioned media and Transwell coculture with C26 or HCT116 tumor cells. Cachectic hiPSC-CMs exhibited atrophy, reduced contraction amplitude, prolonged relaxation time, and elevated oxygen consumption rate, reflecting wasting, contractile dysfunction, and metabolic dysregulation. Mechanistically, suppression of the AKT/mTORC1/S6 signaling axis notably reduced total and p-AKT, decreased the p-S6/S6 ratio, and downregulated RPTOR, which coincided with FOXO1/3 activation and FOXO1 nuclear translocation, promoting downstream atrophic remodeling. Concurrently, Atrogin-1 upregulation reduced calcineurin A, impairing NFAT nuclear translocation, thereby suppressing downstream growth signaling. Increased autophagic flux with an elevated LC3BII/LC3BI ratio accompanied these changes. Following withdrawal of cachexia-inducing stimuli, Atrogin-1 and autophagy markers normalized within 1 week; however, contractile and metabolic impairments persisted, indicating delayed functional recovery. These findings establish the FOXO/Atrogin-1/calcineurin A/NFAT axis, operating within the broader context of AKT/mTORC1 suppression, as a central regulatory mechanism of cachexia-induced cardiac wasting, unveiling a tractable therapeutic target.
Authors
Nora Hosny, Houda Cohen, Mohamed Waleed Elafany, Jeff Schreifels, John Bauer, Rishi Gulati, Brian R. Thompson, Julia C. Liu, Joseph M. Metzger
Abstract
The clinical success of chimeric antigen receptor T cells in treating hematological malignancies has highlighted the immense therapeutic potential of engineering T cells with synthetic receptors. However, the limited availability of tumor-specific antigens and the poor ability of T cells to infiltrate solid tumor cores remain major obstacles for applying this approach to solid tumors. In this study, we identify a subset of CD8+ T cells at inflammatory sites that acquire FcγRI through trogocytosis from infiltrating monocytes, enabling them to perform transient TCR-independent antibody-dependent cellular cytotoxicity (ADCC). Analysis of FcγRI signaling in these T cells revealed that phosphorylation occurs only when antigen density on the membrane exceeds 30 molecules/μm². Exploiting this threshold, we engineered peripheral blood CD8+ T cells to express a modified FcγRI receptor, allowing them to selectively kill tumor cells while largely sparing healthy tissues expressing normal physiological levels of the same antigen. Moreover, expression of FcγRI receptor in T cells was associated with reduced basement membrane interactions, enhancing their capacity to infiltrate tumors and establish long-term immune memory. Collectively, this work establishes T cell–mediated ADCC as a potent therapeutic strategy that leverages antigen density, rather than antigen identity, to achieve selective cancer targeting.
Authors
Alon Richter, Shahar Dotan, Petr Shendrik, Diana Rasoulouniriana, Amichai Zarfin, Nadine Santana-Magal, Aseel Khateeb, Adi Frisch, Gal Verbin, Ariel Galor, Eran Sadot, Oran Zlotnik, Avishai Maliah, Ori Moskowitz, Tom Ben-Dov, Maya Halpern, Chen Luxenburg, Alexander Leithner, Yu Zhang, Natalia T. Freund, Merav Cohen, Carmit Levy, Matthew H. Spitzer, Raya Sorkin, Michael L. Dustin, Peleg Rider, Yaron Carmi
Abstract
Tuberous sclerosis complex (TSC) is an inherited tumor predisposition syndrome caused by pathogenic variants in TSC1 or TSC2, yet no animal model faithfully recapitulates the cardiac rhabdomyomas (CR) that are among its earliest manifestations. We generated a heterozygous TSC2-mutant Yucatan minipig carrying the recurrent pathogenic TSC2 p.Arg505* variant and characterized its cardiac phenotype using histopathology, immunohistochemistry, and RNA sequencing. TSC2-mutant minipigs consistently developed multiple CR that closely resembled human lesions, including enlarged glycogen-rich spider cells and activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Comparative transcriptomic analyses demonstrated enrichment of a conserved TSC-associated gene expression program and activation of microphthalmia/transcription factor E (MITF/TFE)-regulated lysosomal pathways in both human and minipig tumors. Although other manifestations of TSC were not observed during the first year of life, this large-animal model faithfully reproduced the principal histopathologic and molecular features of human CR. These findings have established the TSC2-mutant Yucatan minipig as what we believe to be the first large-animal model of TSC-associated CR and provide a physiologically relevant platform for investigating tumor pathogenesis, mechanisms of spontaneous regression, and therapeutic strategies targeting mTORC1- and MITF/TFE-dependent signaling.
Authors
Elias Bou Farhat, Heng Du, Chrystalle Katte Carreon, Jad Halawi, Sophie Kudler, Magdalena Losko, Zachary T. Herbert, Adrienne L. Watson, Daniel Carlson, Dennis A. Webster, Derek M. Korpela, David M. Meredith, Elizabeth P. Henske, David J. Kwiatkowski
Abstract
Basal-like double-negative prostate cancer (DNPC) and triple-negative breast cancer (TNBC) are aggressive tumors with few targeted treatment options, raising the question of whether a shared, druggable cell-surface antigen can be leveraged for effective immunotherapy. Here, we integrated analyses of independent bulk and single-cell transcriptomic datasets with mechanistic and preclinical therapeutic studies to evaluate CDH3 (P-cadherin) as a candidate target in basal-like disease. CDH3 expression was consistently enriched in basal-like subtypes across prostate and breast cancer cohorts and was preferentially expressed in basal epithelial tumor compartments. Mechanistically, CDH3 expression was governed by a YAP1–WNT5A/ROR2 signaling axis, linking basal subtype gene expression to non-canonical Wnt signaling. To exploit this target, we evaluated both a CDH3-directed antibody-drug conjugate (ADC) and CDH3-specific chimeric antigen receptor (CAR)-T cells. The ADC exhibited antigen-dependent internalization and cytotoxicity in vitro and reduced metastatic tumor burden in vivo. CDH3 CAR-T cells showed antigen-specific activation and tumor cell killing in vitro and improved tumor control and survival in metastatic prostate and breast cancer xenograft models, with additional benefit when combined with PD-1 blockade (nivolumab). Together, these findings establish CDH3 as a clinically relevant and therapeutically actionable target and support CDH3-directed ADC and CAR-T strategies for aggressive, basal-like DNPC and TNBC.
Authors
Guoqiang Liu, Shiyu Wang, Ziyu Zeng, Loan Duong, Jing Yang, Nipuni Barupala, Yun Zhao, Sharif Rahmy, Shan Feng, Xiaotian Chi, Ariana Arce, Linchuan Jia, Jun Wan, Liang Cheng, Xuemin Lu, Xin Lu
Abstract
Authors
Alejandra M. Marinelarena, Thao D. Pham, Jeffrey H. Becker, Apurba Majumder, Hidayatullah G. Munshi
Abstract
Advillin (AVIL) is an actin-binding protein expressed in peripheral sensory neurons and Merkel cells, but aberrantly upregulated in several malignancies, including low-grade glioma, glioblastoma, and rhabdomyosarcoma. AVIL’s oncogenic activity and restricted adult tissue expression make it an attractive therapeutic target; however, its physiological function and the safety of AVIL inhibition remain incompletely understood. We evaluated genetic and pharmacologic targeting of Avil using neurobehavioral and somatosensory assays in vivo. Constitutive and conditional Avil knockout mice, generated by exons 7 and 8 deletion, underwent behavioral testing assessing anxiety-related and exploratory behaviors, motor coordination, affective responses, and learning and memory. Nociceptive and tactile sensory function were evaluated alongside histologic analysis of peripheral mechanosensory architecture. In parallel, a first-in-class AVIL inhibitor was assessed in vivo. Avil-deficient mice exhibited normal exploratory and anxiety-related behavior, intact motor coordination, preserved affective responses, and unaltered learning and memory. Loss or pharmacologic inhibition of advillin did not impair nociceptive processing, tactile sensitivity, or peripheral mechanosensory architecture, and histologic abnormalities were not detected. Together, these findings show preserved baseline behavioral and sensory outcomes following lifelong Avil loss, with complementary evidence of tolerability following pharmacologic inhibition under the conditions tested, supporting AVIL as a potentially well-tolerated therapeutic target in cancer.
Authors
Sarah A. Lynch, Martyna Glowczyk-Gluc, Yiwei Wang, Summer Johnson, Xinrui Shi, Abdul-Salam Gidado, Alexis Johnson, Christopher Deppmann, John Lukens, Hui Li
Abstract
Bone metastases are a frequent complication of breast cancer, leading to reduced quality of life and increased morbidity. By intratibially injecting PyMT breast cancer cells in mice, we showed that the presence in the gut microbiome of segmented filamentous bacteria (SFB), a taxon that induces IL-17–producing Th17 cells and TNF-α (TNF)–producing T cells (TNF+ T cells), accelerated intraosseous tumor growth. SFB increased the activity of parathyroid hormone–related protein (PTHrP), a known driver of breast cancer bone metastasis produced by breast cancer cells. SFB promoted the PTHrP-induced expansion of intestinal Th17 cells and TNF+ T cells, their migration to bone marrow (BM) in tumor-bearing bones, and the BM expression of TNF, IL-17, and RANKL, cytokines that promote bone resorption. Demonstrating the functional relevance of IL-17 and TNF, silencing of either IL-17 or TNF blunted the growth of bone lesions in SFB+ mice. Thus, the abundance of SFB in the microbiome of mice and of SFB-like taxa in humans may determine the potency of PTHrP and the rate of growth of bone metastasis in breast cancer. Targeting the gut microbiota may represent a novel therapeutic strategy for breast cancer bone metastasis.
Authors
Nand K. Roy, Subhashis Pal, Hamid Y. Dar, Sanchiti Patil, M. Neale Weitzmann, Roberto Pacifici
Abstract
Septins are RAS-like GTP-binding proteins involved in cytoskeletal organization and cellular division. We previously described 2 pediatric patients harboring SEPT6 germline mutations (GM1: SEPT6 c.1282T>C and GM2: SEPT6 c.1282T>A) presenting with congenital neutropenia associated with the development of myelodysplastic syndrome. In one patient, an additional somatic mutation (SM: SEPT6 c.43C>T) was detected at a low allelic fraction in the BM. Here, we describe the consequences of these mutations for hematopoiesis. Transgenic expression or gene editing of GM1 or GM2 in human CD34+ cells led to enlarged, multinucleated cells associated with accelerated exhaustion and premature senescence of hematopoietic stem and progenitor cells (HSPCs). Senescence defects were associated with the upregulation of mTOR phosphorylation, and pharmacologic inhibition of the mTOR pathway resulted in rescue of senescence. In parallel, HSPCs exhibited marked mitochondrial abnormalities, including increased expression of OPA-1, a key regulator of mitochondrial fusion, and enhanced oxygen consumption during mitochondrial respiration. Introduction of the SM in cis with GM1 mitigated all observed defects. Collectively, our findings demonstrate a gain-of-function mechanism underlying marrow failure in patients carrying germline SEPT6 mutations and suggest that acquisition of a secondary somatic SEPT6 variant may confer a compensatory effect within hematopoietic cells.
Authors
Safa F. Mohamad, Meaghan McGuinness, Yu Zhou, Xin Jiang, Gabriele Casirati, Adele Mucci, Sara Canovas Nunes, Akiko Shimamura, Pietro Genovese, David A. Williams
Abstract
Matrix stiffness is a hallmark of aggressive solid tumors and strongly associated with therapeutic resistance and poor prognosis. This mechanical barrier represents a major unmet challenge in oncology, as current strategies rarely address how matrix mechanics themselves drive treatment resistance. Here, we identified ferroptosis, an iron-dependent form of cell death, as a potential long-sought vulnerability that can be exploited to eliminate mechanically resistant tumors. Using genetic and chemical approaches, we investigated how matrix stiffness sensitizes cancer cells to ferroptosis and whether this vulnerability can be therapeutically targeted. We found that cancer cells cultured on stiff matrices were more sensitive to ferroptosis than those on soft matrices, as evidenced by reduced cell viability and elevated lipid peroxidation. Furthermore, we found that matrix stiffness induced YAP activation, which upregulated its target gene SKP2, a key mediator required for the heightened ferroptosis sensitivity observed under stiff conditions. Finally, using an injectable hydrogel system, we demonstrated that stiffened tumors were resistant to chemotherapy but remained highly susceptible to ferroptosis induction, resulting in markedly reduced tumor volume and weight. Our findings established ferroptosis as a stiffness-dependent vulnerability mediated by a YAP-SKP2 signaling axis, revealing a mechanotransductive pathway that may be leveraged to target treatment-refractory tumors.
Authors
Emma Villares, Nico Taber, Shao-Chin Wu, Connor Amelung, Jianli Wu, Chao-Chieh Lin, Jen-Tsan Chi, Sharon Gerecht
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