tbuckley/cabot-search huggingface dataset:
Abstract IA025: Targeting the gut microbiome for cancer immunotherapy
Authors: Giorgio Trinchieri
Journal: Cancer Research (2024)

Abstract Growing evidence suggests that the gut microbiota modulates the efficacy and toxicity of cancer therapy, most notably immunotherapy and its immune-related adverse effects. The impaired response to immunotherapy in patients treated with antibiotics supports this role of the microbiota. Until recently, results pertaining to the identification of the microbial species responsible for these effects were incongruent, and relatively few studies analyzed the underlying mechanisms. Gut microbial communities (microbiotypes) with non-uniform geographic distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts Now, a better understanding of the taxonomy of the species involved and of their mechanisms of action has been achieved. Defined bacterial species have been shown to promote a response to immune checkpoint inhibitors through the production of different products or metabolites, although a suppressive effect of Gram(-) bacteria may be dominant in some unresponsive patients. Machine learning approaches trained on patients’ microbiota composition can predict the ability of patients to respond to immunotherapy with some accuracy. Thus, the interest in modulating the microbiota composition to improve patients’ responsiveness to therapy has been mounting. Our data of a fecal microbiota transfer clinical trial in anti-PD1 refractory melanoma patients has provided clinical proof of concept of the possibility to target the gut microbiota composition in cancer therapy. Also, both in clinical studies and in experimental animals, diets rich in fibers improve the response to immunotherapy by modifying the gut microbiome suggesting the possibility of dietary approaches to target the microbiota composition in cancer therapy. However, while many early clinical studies have analyzed the association of the microbiota composition with the response to anti-PD-1 in cancer patients, emerging evidence suggests that the association may be context dependent and different types of mono or combination immunotherapies may be differentially regulated by the microbiota, Thus, a more personalized approach depending original gut microbiota composition of the patients and the type of immunotherapy protocol selected may be necessary for optimal clinical results. Citation Format: Giorgio Trinchieri. Targeting the gut microbiome for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA025.
Abstract C026: TGF-β induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis
Authors: Zhenghan Wang, Yassmin Elbanna, Inês Godet, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué
Journal: Cancer Research (2024)

Abstract Epithelial-to-mesenchymal transition (EMT) plays important roles during development, injury repair, cancer invasion and metastasis. The heterogeneity of EMT programs is manifest in the diverse EMT-like phenotypes occurring during tumor progression. However, little is known about the mechanistic basis and functional role of specific forms of EMT in cancer. Here we address this question in lung adenocarcinoma (LUAD) cells that enter a dormancy period in response to TGF-β upon disseminating to distant sites. Through in vivo selection, we established dormant metastasis models from human and mouse early-stage LUAD cell lines. LUAD cells with the capacity to enter dormancy are characterized by expression of SOX2 and NKX2-1 primitive progenitor markers, whereas cells derived from overt metastases express high level of the late-stage progenitor marker Sox9. Using a TGF-β signaling reporter, we showed that in the primitive progenitors, TGF-β induces growth inhibition accompanied by a classic EMT response that subsequently transitions into an atypical mesenchymal state of round morphology as the disseminated cells establish dormancy. Prolonged treatment with TGF-β in vitro recapitulates this transition in these primitive progenitors, but not in the late-stage progenitors. Given this dramatic morphological change, we focused on actin-cytoskeleton regulators and found that TGF-β induces this transition by driving the expression of the actin-depolymerizing factor gelsolin, which changes a migratory, stress fiber-rich mesenchymal phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors, protecting them from killing by mechanosensitive cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Inhibiting this actin depolymerization process clears tissues of dormant metastatic cells. Thus, LUAD primitive progenitors undergo an atypical EMT as part of a strategy to evade immune-mediated elimination during dormancy. Our results provide a mechanistic basis and functional role of this atypical EMT response of LUAD metastatic progenitors and further illuminate the role of TGF-β as a crucial driver of immune evasive metastatic dormancy. Citation Format: Zhenghan Wang, Yassmin Elbanna, Inês Godet, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué. TGF-β induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C026.
Abstract C052: Induction of senescence by paclitaxel in high-grade serous ovarian carcinoma (HGSOC) cells renders the cells resistant to paclitaxel but sensitizes them to BCL-xL targeting agents
Authors: Yang Yang
Journal: Cancer Research (2024)

Abstract High-grade serous ovarian carcinoma (HGSOC) is a very aggressive form of ovarian cancer, contributing to most ovarian cancer deaths. Paclitaxel is one of the major components of the first line treatment for HGSOC, but the development of chemoresistance to paclitaxel leads to the frequent relapse of the disease and poor prognosis in HGSOC patients. However, the mechanism underlying the chemoresistance has not been well established nor have the strategies to overcome the resistance been developed, which was investigated in the present study using three representative HGSOC cell lines (i.e. Kuramochi, OVCAR4, and OVCAR3 cells) in vitro. The results from our study show that induction of senescence contributes to paclitaxel-induced chemoresistance in HGSOC cells. More importantly, we found that senescent HGSOC cells induced by paclitaxel became highly dependent on BCL-xL for survival and thus were very sensitive to BCL-xL targeting agents, particularly to DT2216 (a BCL-xL specific proteolysis targeting chimera or PROTAC) and 753b (a BCL-xL and BCL-2 dual PROTAC). Because these PROTACs are more potent against senescent HGSOC cells but less toxic to platelets than ABT263 (a BCL-xL and BCL-2 dual inhibitor), they have the potential to be developed as new senolytics to overcome HGSOC chemoresistance to paclitaxel without causing the on-target and dose-limiting thrombocytopenia associated with ABT263 treatment. Citation Format: Yang Yang. Induction of senescence by paclitaxel in high-grade serous ovarian carcinoma (HGSOC) cells renders the cells resistant to paclitaxel but sensitizes them to BCL-xL targeting agents [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C052.
Abstract IA016: Vascular control of metastasis
Authors: Hellmut G. Augustin
Journal: Cancer Research (2024)

Abstract The molecular analysis of tumor vessel interactions during tumor progression and metastasis has primarily focused on the study of tumor cell-derived angiogenic and lymphangiogenic signals with the purpose to exploit such factors as therapeutic targets. Angiogenic factors activate endothelial cells in nearby blood and lymphatic capillaries to sprout towards the tumor. Tumor angiogenesis thereby not only nourishes the growing tumor, but access to the blood and lymphatic vasculatures enables cells from the primary tumor to enter the circulation to eventually form metastases at distant sites. The complex cellular interactions between tumor cells and endothelial cells have in this context mostly been studied from a tumor cell-centric perspective, i.e., the tumor cells send signals to which endothelial cells merely respond. Yet, the past decade has witnessed a fundamental change of paradigm with the discovery that the vascular endothelium does not just respond to exogenous cytokines but exerts active ’angiocrine’ gatekeeper roles controlling their microenvironment in an instructive manner. We have applied the concepts of angiocrine signaling towards the study of tumor progression and metastasis. Employing novel surgical preclinical metastasis models that better mimic tumor progression and the response to therapy as it occurs in humans, we have molecularly dissected vascular endothelial cells in progressing primary tumors as well as in the pre-metastatic and metastatic niches. These experiments were on the one hand aimed at establishing the systems map of endothelial transcriptomic changes during tumor progression and metastasis and on the other hand to identify and validate novel therapeutic targets. This presentation will review recent advances in the field of tumor microenvironment research and present novel angiocrine signaling mechanisms as promising targets of future mechanism-driven anti-metastatic therapy. Citation Format: Hellmut G. Augustin. Vascular control of metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA016.
Abstract IA014: Unraveling pancreatic tumor defenses: inside the stromal orchestra with the HOST-factor
Authors: Edna Cukierman
Journal: Cancer Research (2024)

Abstract Dive into how members of the Cukierman lab and their collaborators explore desmoplasia, the dense “shield” around tumors. Discover their groundbreaking 3D model that reveals the intricate “symphony” of fibroblasts and the interstitial extracellular matrix they produce. Learn how these elements impact cancer cells, as well as the function of immune and other tumor microenvironment cells. Central to the lab’s research is the HOST-Factor (Harmonic Output of Stromal Traits), a new tool to measure and eventually modify the microenvironment’s influence on tumors. Don’t miss this opportunity to see how the team is transforming our understanding of pancreatic cancer’s onset, progression, and treatment responses. Citation Format: Edna Cukierman. Unraveling pancreatic tumor defenses: inside the stromal orchestra with the HOST-factor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA014.
Abstract C023: P21-positive senescent stromal cells promote prostate cancer immune suppression and progression that can be reversed by senolytic therapy
Authors: Lin Zhou, Kelly D. DeMarco, Katherine C. Murphy, Zhenpeng Wu, Jinping Li, Junhui Li, Calvin Johnson, Zhong Jiang, Shi Bai, Tianyi Ye, Karl Simin, Lihua Julie Zhu, Jason R Pitarresi, Hong Wu, Marcus Ruscetti
Journal: Cancer Research (2024)

Abstract Cellular senescence is historically viewed as a tumor-suppressive cell cycle arrest program to limit outgrowth of pre-malignant cells. However, emerging evidence suggests senescent cell persistence contributes to immune suppression and cancer progression. Using prostate cancer patient samples and murine models, we find that p16+ senescent cells accumulate throughout malignant progression and are associated with immune suppression and poor survival. p16 ablation in mice eliminated senescent epithelial cells and reversed immune suppression mediated by immature myeloid cells but not prostate tumorigenesis. Single cell sequencing revealed an additional population of senescent p21+ fibroblasts and myeloid cells. Targeting BCL-xL or PD-L1 induced during senescence could remove both p16+ epithelial and p21+ stromal senescent cells, reactivate T cell immunity, and block tumor initiation as well as progression in advanced prostate cancer models. Our findings demonstrate that targeting heterogenous senescent populations can not only prevent malignant transformation but also yield therapeutic benefits in advanced prostate cancers through activating anti-tumor immunity. Citation Format: Lin Zhou, Kelly D. DeMarco, Katherine C. Murphy, Zhenpeng Wu, Jinping Li, Junhui Li, Calvin Johnson, Zhong Jiang, Shi Bai, Tianyi Ye, Karl Simin, Lihua Julie Zhu, Jason R Pitarresi, Hong Wu, Marcus Ruscetti. P21-positive senescent stromal cells promote prostate cancer immune suppression and progression that can be reversed by senolytic therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C023.
Abstract C018: Awakened dormant cancer cells undergo highly mesenchymal to quasi- mesenchymal transition and acquire stemness
Authors: Jingwei Zhang, Robert Weinberg
Journal: Cancer Research (2024)

Abstract The awakening of dormant disseminated cancer cells is likely responsible for the clinical relapses of patients whose primary tumors have been cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, non-proliferative phenotypic state. The awakening of these cells does not occur by a cancer cell-autonomous process. Instead, inflammation and wound healing of the surrounding tissue microenvironment causes them to shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire stemness and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their stemness, doing so without ongoing heterotypic signaling from the lung microenvironment. EGFR ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is essential for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse. Citation Format: Jingwei Zhang, Robert Weinberg. Awakened dormant cancer cells undergo highly mesenchymal to quasi- mesenchymal transition and acquire stemness [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C018.
Abstract C031: Targeting colorectal cancer-associated fibroblasts with all-trans retinoic acid to reprogram the tumor microenvironment
Authors: Brandon Choi, Yuyuan Zhou, Seungil Kim, Shannon M. Mumenthaler
Journal: Cancer Research (2024)

Abstract Cancer-associated fibroblasts (CAFs) are a prominent component of the tumor microenvironment (TME) and are known for their role in supporting tumor growth and progression through interactions with cancer cells and other stromal elements. Liver metastatic CAFs (lmCAFs), in particular, play an important role in establishing the secondary niche that facilitates tumor metastasis. Reprogramming the stroma, particularly targeting the pro-tumorigenic functions of lmCAFs, has emerged as a promising therapeutic intervention to disrupt the supportive environment tumors rely on for progression. An initial drug screen of FDA-approved oncology therapies was conducted on patient-derived colorectal cancer (CRC) CAFs and tumor organoids (PDTOs) to identify compounds that may be re-purposed as stroma targeting agents. All-trans retinoic acid (ATRA) was shown to specifically inhibit the proliferation of CAFs without affecting CRC-PDTOs. ATRA is an active metabolite of Vitamin A that exerts its canonical biological effects by binding to nuclear retinoic acid receptors (RAR). The differential RAR expression in multiple CAFs and PDTOs was confirmed with bulk RNA sequencing, with higher expression found in the CAF lines. Subsequent analysis included the qPCR assessment of glycolysis enzyme levels, CAF activation markers, and ATRA signaling in lmCAFs following treatment with ATRA for 5 days. Protein expression of key components of the TGF-b signaling pathway, including SMAD 2/3, Akt, and b-catenin, were also analyzed. Treatment of lmCAFs with ATRA induced expression of RARb and ALDH1A1, biomarkers associated with ATRA signaling pathways. In one patient-derived CAF line, ATRA treatment exhibited a decrease in CAF activation markers (e.g. aSMA) and glycolytic enzymes (e.g. lactate dehydrogenase). On the other hand, another CAF line showed increased fibroblast activation and a shift away from metabolic dependency on glycolysis upon ATRA treatment. Additionally, ATRA targeted TGF-b signaling through the pSMAD 2/3 and Akt pathways, highlighting the multifaceted impact on CAF function and heterogeneity. ATRA effectively reprograms some CAFs by inhibiting their proliferation and altering key signaling pathways, thereby disrupting the pro-tumorigenic environment of the TME. The results of this study suggest that ATRA holds potential as a therapeutic strategy to target and reprogram the CAFs within the permissive stromal components essential for tumor progression. Citation Format: Brandon Choi, Yuyuan Zhou, Seungil Kim, Shannon M. Mumenthaler. Targeting colorectal cancer-associated fibroblasts with all-trans retinoic acid to reprogram the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C031.
Abstract PR012: KRAS mutation-specific effects on the tumor immune microenvironment drive tumor progression in pancreatic cancer
Authors: Andrew Wenger, Tal Baron, Erika Hissong, Rohit Chandiwani, Lukas Dow, Despina Siolas, Katherine Bacchi, Huanhuan Sun, Erika Hissong, Adrian Vega, Whitney Sisso, Kawther Abdilleh
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with abysmal survival rates. The highly immunosuppressive microenvironment of PDAC poses a major barrier to effective therapy. KRAS mutations are near-ubiquitous in PDAC, and studies indicate clinical outcomes vary depending on the specific KRAS genotype. Given that tumor genotype can shape the immune cell composition of tumors, we examined the immune cell composition of pancreatic tumors with specific KRAS mutations, focusing on KRASG12D mutations (representing 40% of PDAC cases which have the worst prognosis) and KRASG12R mutations (which make up 20% of PDAC cases and have a better prognosis). Orthotopically implanted Kras G12R/+ ;Trp53 KO mouse pancreatic tumors have a distinct immune profile in comparison to Kras G12D/+ ;Trp53 KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. Selective depletion of CD4+ T cells induces a rapid progression in KRASG12R, but not KRASG12D mouse tumors. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available and real-world human PDAC datasets and enrichment of dendritic cells and other immune related cell types in KRASG12R tumors. Collectively, these data link the KRASG12R mutation to a unique immunogenic role. Citation Format: Andrew Wenger, Tal Baron, Erika Hissong, Rohit Chandiwani, Lukas Dow, Despina Siolas, Katherine Bacchi, Huanhuan Sun, Erika Hissong, Adrian Vega, Whitney Sisso, and Kawther Abdilleh. KRAS mutation-specific effects on the tumor immune microenvironment drive tumor progression in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR012.
Abstract IA007: Respiratory viral infection promotes the awakening and outgrowth of dormant metastatic breast cancer cells in lungs
Authors: Shi B. Chia, Bryan J. Johnson, Junxiao Hu, Roel Vermeulen, Marc Chadeau-Hyam, Fernando Guntoro, Hugh Montgomery, Meher Boorgula, Varsha Sreekanth, Andrew Goodspeed, Bennett Davenport, Felipe Valenca-Pereira, Vadym Zaberezhnyy, Wolfgang E Schleicher, Dexiang Gao, Andreia N. Cadar, Michael Papanicolaou, Afshin Beheshti, Stephen B. Baylin, James Costello, Jenna M. Bartley, Thomas E. Morrison, Julio A. Aguirre-Ghiso, Mercedes Rincon, James DeGregori
Journal: Cancer Research (2024)

Abstract Breast cancer is the second most common cancer globally. Most deaths from breast cancer are due to metastatic disease which often follows long periods of clinical dormancy. Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCC) is crucial for addressing metastatic progression. Infection with respiratory viruses (e.g. influenza or SARS-CoV-2) is common and triggers an inflammatory response locally and systemically. Here we show that influenza virus infection leads to loss of the pro-dormancy mesenchymal phenotype in breast DCC in the lung, causing DCC proliferation within days of infection, and a greater than 100-fold expansion of carcinoma cells into metastatic lesions within two weeks. Such DCC phenotypic change and expansion is interleukin-6 (IL-6)-dependent. We further show that CD4 T cells are required for the maintenance of pulmonary metastatic burden post-influenza virus infection, in part through attenuation of CD8 cell responses in the lungs. Single-cell RNA-seq analyses reveal DCC-dependent impairment of T-cell activation in the lungs of infected mice. SARS-CoV-2 infected mice also showed increased breast DCC expansion in lungs post-infection. Expanding our findings to human observational data, we observed that cancer survivors contracting a SARS-CoV-2 infection have substantially increased risks of lung metastatic progression and cancer-related death compared to cancer survivors who did not. These discoveries underscore the significant impact of respiratory viral infections on the resurgence of metastatic cancer, offering novel insights into the interconnection between infectious diseases and cancer metastasis. Citation Format: Shi B. Chia, Bryan J. Johnson, Junxiao Hu, Roel Vermeulen, Marc Chadeau-Hyam, Fernando Guntoro, Hugh Montgomery, Meher Boorgula, Varsha Sreekanth, Andrew Goodspeed, Bennett Davenport, Felipe Valenca-Pereira, Vadym Zaberezhnyy, Wolfgang E Schleicher, Dexiang Gao, Andreia N. Cadar, Michael Papanicolaou, Afshin Beheshti, Stephen B. Baylin, James Costello, Jenna M. Bartley, Thomas E. Morrison, Julio A. Aguirre-Ghiso, Mercedes Rincon, James DeGregori. Respiratory viral infection promotes the awakening and outgrowth of dormant metastatic breast cancer cells in lungs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA007.