Oncology
Abstract
Patients with estrogen receptor+ (ER+, ESR1+) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1, mirroring the 2 most common mutations seen in patients. ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.
Authors
Yu Gu, Dongmei Zuo, Qi-Xin Hu, Virginie Sanguin-Gendreau, Alain Pacis, Marie-Christine Guiot, Alexander Chih-Chieh Chang, Tarek Taifour, Chen Ling, Adrian V. Lee, Steffi Oesterreich, William J. Muller
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) with pancreatic metastases (PM) is paradoxically associated with prolonged overall survival (OS), but the biological basis for this observation remains unclear.METHODS We analyzed matched primary and metastatic samples from an international consortium of patients with PM (n = 108) and compared them with a previously characterized ccRCC cohort without PM (n = 273).RESULTS Primary ccRCC tumors associated with PM were dominated by indolent, angiogenic phenotypes, characterized by low-grade histology and reduced mTORC1 activation (all P < 0.001). Tumors of patients with PM were often PBRM1-deficient (80.4% vs. 54.8%, P < 0.001) and rarely harbored BAP1 loss (3.7% vs. 20.7%, P < 0.001). After metastasis diagnosis, patients with PM had significantly longer median OS compared with those without PM (110 vs. 33 months, HR 0.28 [95% CI, 0.19–0.39], P < 0.001). Survival was further prolonged among patients with PBRM1 loss (143 vs. 64 months, HR 0.41 [95% CI, 0.22–0.81], P = 0.008). Notably, PM lesions were typically low-grade and PBRM1-deficient even when more aggressive and evolved clones were present in primary tumors. Finally, PBRM1 loss was associated with preferential response to angiogenesis inhibitors over immune-oncology therapy, reflected by longer time on treatment (32.1 vs. 9.1 months, HR 0.16 [95% CI, 0.06–0.39], P < 0.001).CONCLUSION These findings illustrate selective tropism of indolent, less-evolved, PBRM1-deficient ccRCC clones for pancreatic dissemination. This biological bias likely underlies therapeutic sensitivity and favorable survival, supporting the consideration of PBRM1 status and metastatic tropism in risk stratification and treatment selection.FUNDING NIH Kidney Cancer SPORE grant (P50CA196516); The Cancer Prevention and Research Institute of Texas (RP220294); Endowment from Jan and Bob Pickens Distinguished Professorship in Medical Science and Brock Fund for Medical Science Chair in Pathology.
Authors
Haitao Xu, Payal Kapur, Alana Christie, Aleksandra W. Nielsen, Averi Perny, Olivia Brandenburg, Charlotte Small, Jeffrey Miyata, Hua Zhong, Courtney Roberts, Roy Elias, Vanina Tcheuyap, Cassandra Duarte, Adrie van Bokhoven, Justine Panian, Haoran Li, Katharine A Collier, Debra Zynger, Luis Meza, Benoit Beuselinck, Neeraj Agarwal, Amir Mortazavi, Sumanta Pal, Rana McKay, Elaine T. Lam, Satwik Rajaram, James Brugarolas
Abstract
Mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) have been considered late acquired mutations in acute myeloid leukemia (AML) development. Using single-cell DNA sequencing, we found that PTPN11 mutations can occur as initiating events in some patients with AML when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The resulting AML has a diverse set of variably differentiated myeloid cells with few myeloid cells that lack leukemic mutations. The role of Ptpn11 as a codriver was confirmed in a murine model that exhibits an AML phenotype with a comparable immune diversity that is serially engraftable and reconstituted from early precursor cells. Furthermore, lineage-negative bone marrow cells from these mice reconstitute the full diversity of mature myeloid cells, and these cells exhibit an altered cytokine response after physiologic stimulation. Our work highlights how PTPN11-mutated AML is derived from a multitude of codominant and late acquired aberrations that have a previously unrecognized differentiated myeloid clonal expansion potentially contributing to pathogenesis of the disease.
Authors
Sydney Fobare, Chia Sharpe, Kate Quinn, Kinsey Bryant, Linde A. Miles, Robert L. Bowman, Carolyn Cheney, Casie Furby, Marissa Long, Kaytlynn Fyock, Ben Wronowski, James R. Lerma, Krzysztof Mrózek, Deedra Nicolet, Thomas M. Sesterhenn, Megan E. Johnstone, Jianmin Pan, Shesh N. Rai, Chandrashekhar Pasare, Nives Zimmermann, Wen-Mei Yu, Cheng-Kui Qu, Andrew Carroll, Richard Stone, Eunice S. Wang, Jonathan Kolitz, Bayard Powell, John P. Perentesis, Ann-Kathrin Eisfeld, Erin Hertlein, John C. Byrd
Abstract
Pancreatic cancer is a highly innervated gastrointestinal disease in which sympathetic nerves play a critical role in modulating tumor growth and the tumor microenvironment (TME). While recent studies suggest that sympathetic nerves influence various TME components, including lymphoid and myeloid immune cells, their interactions with cancer-associated fibroblasts (CAFs) remain poorly understood. CAFs are a hallmark of pancreatic tumors and are known to upregulate axon guidance and neuroactive cues, suggesting a potential feedback loop with tumor-innervating nerves. Here, we investigated the bidirectional crosstalk between sympathetic nerves and CAFs in human and mouse pancreatic tumors. Using a chemo-genetic ablation model, we selectively eliminated pancreatic sympathetic nerves and found that denervation significantly reduced tumor size in female mice. To further dissect this interaction, we established co-culture systems with immortalized pancreatic fibroblasts and primary sympathetic neuron explants, identifying key transcriptional changes driven by CAF-sympathetic nerve signaling. Our findings demonstrated that sympathetic signaling enhanced CAF activation and extracellular matrix remodeling, while activated CAFs, in turn, induced transcriptional programs in sympathetic neurons associated with nerve injury response. These results establish CAFs as central mediators of the tumor-supportive role of sympathetic nerves, offering further insights into the neural regulation of pancreatic cancer progression.
Authors
Ariana L. Sattler, Parham Diba, Kevin Hawthorne, Carl Pelz, Joe Grieco, Tetiana Korzun, Bryan Chong, M.J. Kuykendall, Rosalie C. Sears, Daniel L. Marks, Mara H. Sherman, Teresa A Zimmers, S. Ece Eksi
Abstract
The contribution of 9p deletion to B-cell acute lymphoblastic leukemia (B-ALL) has remained elusive since its discovery more than 40 years ago. Here we show that loss of CD72 is recurrent in B-ALL cases containing PAX5 deletions, and that Cd72 haploinsufficiency drives B-ALL development in Pax5+/− mice. Mechanistically, Cd72+/-;Pax5+/- precursor B cells exhibit an inflammatory transcriptional profile characterized by a decrease in Myd88 expression, a finding that aligns with our previous studies of B-ALL development in Pax5+/- mice following exposure to immune stressors. These combined genomic analyses and functional models provide compelling evidence that co-deletion of two contiguous genes, Pax5 and Cd72, drives B-cell leukemogenesis.
Authors
Belén Ruiz-Corzo, Ana Casado-García, Ninad Oak, Paula Somoza-Cotillas, Andrea López-Álvarez de Neyra, Jorge Martínez-Cano, Alba Pérez-Pons, Elena G. Sánchez, Oscar Blanco, Diego Alonso-López, Javier De Las Rivas, Susana Riesco, Pablo Prieto-Matos, Francisco Javier Garcia-Criado, Maria Begoña Garcia-Cenador, Alberto Orfao, Manuel Ramírez-Orellana, César Cobaleda, Carolina Vicente-Dueñas, Kim E. Nichols, Isidro Sánchez-García
Abstract
Sarcomas are a heterogeneous group of cancers with few shared therapeutic targets. We show that PI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30-60%), representing a common therapeutic target. The PI3K pathway has lacked a downstream oncogenic transcription factor. We show TAZ and YAP are transcriptional co-activators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. This PI3K-TAZ/YAP axis exists in parallel to the known PI3K-Akt-mTORC1 axis providing a rationale for combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1. Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage dependent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. Furthermore, this combination therapy showed a synergistic effect in vivo, suggesting that an integrated view of PI3K and Hippo signaling can be leveraged therapeutically in PI3K activated sarcomas.
Authors
Keith C. Garcia, Ali A. Khan, Krishnendu Ghosh, Souradip Sinha, Nicholas Scalora, Gillian DeWane, Colleen Fullenkamp, Nicole Merritt, Yuliia Drebot, Samuel Y. Yu, Mariah Leidinger, Michael D. Henry, Patrick J. Breheny, Michael S. Chimenti, Munir R. Tanas
Abstract
Germline and somatic changes in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1- and DGCR8-mutated thyroid lesions using multiomic profiling on over 30 DICER1-/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic changes, which when combined with enhanced downregulation of miRNAs distinguished DICER1-/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA-encoding genes characterized DICER1-/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related changes. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis-related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.
Authors
Anne-Sophie Chong, Carla Roca, Paula Morales-Sánchez, Eduard Dorca, Verónica Barea, Ignacio Ruz-Caracuel, Pablo Valderrabano, Carlota Rovira, Cristina Jou, Dorothée Bouron-Dal Soglio, Rebecca D. Chernock, Giovana T. Torrezan, Marc Pusztaszeri, José M. Cameselle-Teijeiro, Xavier Matias-Guiu, Clara V. Alvarez, Héctor Salvador, Jonathan D. Wasserman, Luis Javier Leandro-García, William D. Foulkes, Eduardo Andrés-León, Paula Casano-Sancho, Barbara Rivera
Abstract
Immunosuppression and metastasis are critical hallmarks of breast cancer, often linked to poor patient outcomes. The secreted cytokine chitinase-3 like 1 (CHI3L11) is frequently overexpressed in breast cancer samples and promotes an immunosuppressed tumor microenvironment. Notably, CHI3L1 expression is elevated in metastatic patient samples when compared to the matched primary breast tumor. To investigate its role in breast cancer metastasis, we generated an inducible Genetically Engineered Mouse Model (GEMM) that overexpresses CHI3L1 in the mammary epithelium. Ectopic expression of CHI3L1 in the Polyomavirus Middle T (PyMT) mouse model of breast cancer suppressed anti-tumor immune responses, accelerated mammary tumor onset and enhanced lung metastasis. Mechanistically, elevated CHI3L1 expression in the mammary epithelium enhanced neutrophil recruitment, which subsequently degraded the extracellular matrix and increased the number of circulating tumor cells. These findings reveal a key mechanism driving metastatic dissemination and argue that therapeutically targeting Chi3l1 could enhance anti-tumor immunity and suppress metastasis.
Authors
Tarek Taifour, Adéline Massé, Yu Gu, Virginie Sanguin-Gendreau, Dongmei Zuo, Bin Xiao, Emilie Solymoss, Yunyun Shen, Hailey Proud, Sherif Samer Attalla, Vasilios Papavasiliou, Nancy U. Lin, Melissa E. Hughes, Kalie Smith, Chun Geun Lee, Suchitra Kamle, Josie Ursini-Siegel, Jack A. Elias, Peter M. Siegel, Rinath Jeselsohn, William J. Muller
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
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