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A Phase 0, Window of Opportunity Study of Parasympathetic Stimulation with Bethanechol in Localized Pancreatic Adenocarcinoma Prior to Surgery
White, Ruth A; Mezzano-Robinson, Valeria; Shi, Qiongyu; Kuriakose, Nadine; Schrope, Beth; Kluger, Michael D; Sugahara, Kazuki; Chabot, John; Manji, Gulam; Oberstein, Paul; Remotti, Helen; Wang, Timothy C; Bates, Susan E
BACKGROUND:The parasympathetic branch of the autonomic nervous system has shown tumor-suppressive effects in preclinical models of pancreatic adenocarcinoma (PDAC) by inhibiting cancer stem cells and suppressing inflammatory cytokine production. Based on these findings, we hypothesized that bethanechol, an FDA-approved parasympathomimetic agent targeting muscarinic receptors, could enhance treatment efficacy in PDAC. METHODS:We conducted a Phase 0/window of opportunity study evaluating short term parasympathetic activation with fixed dose bethanechol (100 mg twice daily) in subjects with resectable or borderline resectable PDAC prior to surgery. The primary endpoint was change in cell proliferation by Ki-67 expression compared to stage matched controls. Secondary endpoints included tissue expression of stem cell markers (CD44), infiltrating immune cells (CD8a, Granzyme B, and CD68), and changes in circulating inflammatory cytokine concentrations. RESULTS:Seventeen patients were enrolled with 13 eligible for analysis of endpoints. Median age was 74 (59-86), 6 female (46%), all ECOG 0-1 and median duration of treatment was 8 days (7-13). R0 resections were achieved in 9 patients (69%). There was no difference in Ki67 and CD44 tissue biomarkers between bethanechol-treated and control samples. Decreased numbers of Granzyme B-expressing cells were seen in bethanechol-treated tissues. Bethanechol treatment was associated with suppression of circulating IL-18. The most common treatment related adverse events (TRAE) were hot flashes (30.7%), urinary frequency (15.4%), increased salivation (15.4%), hyperhidrosis (7.7%), and nausea (7.7%). There were no Grade 3 or higher adverse effects. No surgical complications were attributed to bethanechol treatment. CONCLUSION/CONCLUSIONS:Bethanechol 100 mg twice daily is well tolerated in patients with PDAC in this small phase 0/window of opportunity study (NCT03572283). Bethanechol treatment was associated with decreased Granzyme B positive cells and decreased circulating IL-18 consistent with an anti-inflammatory role for parasympathetic muscarinic signaling in PDAC.
PMID: 40448309
ISSN: 1549-490x
CID: 5854602
Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression
Kobayashi, Hiroki; Iida, Tadashi; Ochiai, Yosuke; Malagola, Ermanno; Zhi, Xiaofei; White, Ruth A; Qian, Jin; Wu, Feijing; Waterbury, Quin T; Tu, Ruhong; Zheng, Biyun; LaBella, Jonathan S; Zamechek, Leah B; Ogura, Atsushi; Woods, Susan L; Worthley, Daniel L; Enomoto, Atsushi; Wang, Timothy C
Cancer-associated fibroblasts (CAFs) and nerves, components of the tumor microenvironment, have each been shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer (CRC) norepinephrine induces ADRB2-dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intra-tumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates CRC growth through ADRA2A/Gi-mediated activation of Yes-Associated Protein (YAP). NGF from CAFs directly enhances CRC cell growth via the PI3K/AKT pathway. Treatment with a tropomyosin receptor kinase (Trk) inhibitor decreased YAP and AKT activation and CRC progression in mice. In human CRC, high NGF expression is associated with the mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF-nerve crosstalk in promoting CRC progression. Blocking this feedforward loop with a Trk inhibitor may represent a potential therapeutic approach for CRC.
PMID: 39137067
ISSN: 2159-8290
CID: 5726812
An optimized protocol for isolation of murine pancreatic single cells with high yield and purity
Wu, Feijing; Jiang, Zhengyu; Qian, Jin; Kobayashi, Hiroki; Waterbury, Quin T; White, Ruth A; Ochiai, Yosuke; Zhi, Xiaofei; Tu, Ruhong; Zheng, Biyun; Shi, Qiongyu; Zamechek, Leah B; Wang, Timothy C
Here, we present a protocol for rapidly isolating single cells from the mouse pancreas, minimizing damage caused by digestive enzymes in exocrine cells. We guide you through steps to optimize the dissection sequence, enzyme composition, and operational procedures, resulting in high yields of viable pancreatic single cells. This protocol can be applied across a wide range of research areas, including single-cell sequencing, gene expression profiling, primary cell culture, and even the development of spheroids or organoids. For complete details on the use and execution of this protocol, please refer to Jiang et al. (2023).1.
PMCID:10826419
PMID: 38219150
ISSN: 2666-1667
CID: 5673102
Sensory nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs
Darragh, Laurel B; Nguyen, Alexander; Pham, Tiffany T; Idlett-Ali, Shaquia; Knitz, Michael W; Gadwa, Jacob; Bukkapatnam, Sanjana; Corbo, Sophia; Olimpo, Nicholas A; Nguyen, Diemmy; Van Court, Benjamin; Neupert, Brooke; Yu, Justin; Ross, Richard B; Corbisiero, Michaele; Abdelazeem, Khalid N M; Maroney, Sean P; Galindo, David C; Mukdad, Laith; Saviola, Anthony; Joshi, Molishree; White, Ruth; Alhiyari, Yazeed; Samedi, Von; Van Bokhoven, Adrie; St John, Maie; Karam, Sana D
BACKGROUND:Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). This prompted an investigation into how nerves within the tumor microenvironment affect the adaptive immune system and tumor growth. METHODS:We used RNA sequencing analysis of human tumor tissue from a recent HNSCC clinical trial, proteomics of human nerves from HNSCC patients, and syngeneic orthotopic murine models of HPV-unrelated HNSCC to investigate how sensory nerves modulate the adaptive immune system. FINDINGS/RESULTS:Calcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking sensory nerve function surgically, pharmacologically, or genetically increased CD8 and CD4 T cell activity in vivo. CONCLUSIONS:Our data support sensory nerves playing a role in accelerating tumor growth by directly acting on the adaptive immune system to decrease Th1 CD4 T cells and activated CD8 T cells in the TME. These data support further investigation into the role of sensory nerves in the TME of HNSCC and points toward the possible treatment efficacy of blocking sensory nerve function or specifically inhibiting CGRP release or activity within the TME to improve outcomes. FUNDING/BACKGROUND:1R01DE028282-01, 1R01DE028529-01, 1P50CA261605-01 (to S.D.K.), 1R01CA284651-01 (to S.D.K.), and F31 DE029997 (to L.B.D.).
PMCID:10939743
PMID: 38423011
ISSN: 2666-6340
CID: 5806332
Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis
Jiang, Zhengyu; Wu, Feijing; Laise, Pasquale; Takayuki, Tanaka; Na, Fu; Kim, Woosook; Kobayashi, Hiroki; Chang, Wenju; Takahashi, Ryota; Valenti, Giovanni; Sunagawa, Masaki; White, Ruth A; Macchini, Marina; Renz, Bernhard W; Middelhoff, Moritz; Hayakawa, Yoku; Dubeykovskaya, Zinaida A; Tan, Xiangtian; Chu, Timothy H; Nagar, Karan; Tailor, Yagnesh; Belin, Bryana R; Anand, Akanksha; Asfaha, Samuel; Finlayson, Michael O; Iuga, Alina C; Califano, Andrea; Wang, Timothy C
While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreERT2-targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2+ cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic KrasG12D-targeted Tff2+ cells are resistant to PDAC initiation. However, KrasG12D activation in Tff2+ cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2+ cells prior to KrasG12D activation in Mist1+ acinar or Dclk1+ FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.
PMID: 37541213
ISSN: 1875-9777
CID: 5673092
Tumor Growth Rate Informs Treatment Efficacy in Metastatic Pancreatic Adenocarcinoma: Application of a Growth and Regression Model to Pivotal Trial and Real-World Data
Yeh, Celine; Zhou, Mengxi; Sigel, Keith; Jameson, Gayle; White, Ruth; Safyan, Rachael; Saenger, Yvonne; Hecht, Elizabeth; Chabot, John; Schreibman, Stephen; Juzyna, Béata; Ychou, Marc; Conroy, Thierry; Fojo, Tito; Manji, Gulam A; Von Hoff, Daniel; Bates, Susan E
BACKGROUND:Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. METHODS:We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. RESULTS:g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. CONCLUSIONS:Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development.
PMCID:9907043
PMID: 36367377
ISSN: 1549-490x
CID: 5673082
Future directions in preclinical and translational cancer neuroscience research
Demir, Ihsan Ekin; Mota Reyes, Carmen; Alrawashdeh, Wasfi; Ceyhan, Güralp O; Deborde, Sylvie; Friess, Helmut; Görgülü, Kıvanç; Istvanffy, Rouzanna; Jungwirth, David; Kuner, Rohini; Maryanovich, Maria; Na'ara, Shorook; Renders, Simon; Saloman, Jami L; Scheff, Nicole N; Steenfadt, Hendrik; Stupakov, Pavel; Thiel, Vera; Verma, Divij; Yilmaz, Bengi Su; White, Ruth A; Wang, Timothy C; Wong, Richard J; Frenette, Paul S; Gil, Ziv; ,; Davis, Brian M
Recent advances in cancer neuroscience necessitate the systematic analysis of neural influences in cancer as potential therapeutic targets in oncology. Here, we outline recommendations for future preclinical and translational research in this field.
PMCID:8315010
PMID: 34327335
ISSN: 2662-1347
CID: 5673152
Nerves on tr[ac]k to support pancreatic cancer metabolism [Comment]
White, Ruth A; Wang, Timothy C
PMID: 33536521
ISSN: 1748-7838
CID: 5673162
Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression
Takahashi, Ryota; Macchini, Marina; Sunagawa, Masaki; Jiang, Zhengyu; Tanaka, Takayuki; Valenti, Giovanni; Renz, Bernhard W; White, Ruth A; Hayakawa, Yoku; Westphalen, C Benedikt; Tailor, Yagnesh; Iuga, Alina C; Gonda, Tamas A; Genkinger, Jeanine; Olive, Kenneth P; Wang, Timothy C
OBJECTIVE:Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1β (IL-1β) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1β and chronic pancreatitis might contribute to PDAC progression. DESIGN/METHODS:-Cre (KC) mice with transgenic mice overexpressing IL-1β to generate KC-IL1β mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples. RESULTS:B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival. CONCLUSION/CONCLUSIONS:We show here that IL-1β promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.
PMID: 32393543
ISSN: 1468-3288
CID: 4520972
PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice
Kim, Woosook; Chu, Timothy H; Nienhüser, Henrik; Jiang, Zhengyu; Del Portillo, Armando; Remotti, Helen E; White, Ruth A; Hayakawa, Yoku; Tomita, Hiroyuki; Fox, James G; Drake, Charles G; Wang, Timothy C
BACKGROUND & AIMS:Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death-1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1. METHODS:Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral-corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti-PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage. RESULTS:T cells, and increased the response of tumors to anti-PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs. CONCLUSIONS:T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 by gastric epithelial cells increases tumorigenesis in response to MNU and H felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.
PMID: 33129844
ISSN: 1528-0012
CID: 5673062