bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒09‒18
35 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. A dormancy mechanism limits metastasis of early spreading cancer cells.
  2. Cell Competition Shapes Metastatic Latency and Relapse.
  3. Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.
  4. Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis.
  5. Targeting lineage plasticity overcomes chemoresistance.
  6. MEX3C-mediated decay of SOCS3 mRNA promotes JAK2/STAT3 signaling to facilitate metastasis in hepatocellular carcinoma.
  7. Loss of epigenetic regulation disrupts lineage integrity, induces aberrant alveogenesis and promotes breast cancer.
  8. Metabolic regulation of Cathepsin B in tumor macrophages drives their pro-metastatic function.
  9. PKN3: a target in cancer metastasis.
  10. Getting a handle on KRAS inhibitor resistance with hapten-mediated anti-tumor immunity.
  11. Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer.
  12. WNT5A-RHOA signaling is a driver of tumorigenesis and represents a therapeutically actionable vulnerability in small cell lung cancer.
  13. Phenomenological Approach to Cancer Cell Persistence.
  14. Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites.
  15. The Clinical Landscape of Cell-Free DNA Alterations in 1,671 Patients with Advanced Biliary Tract Cancer.
  16. Hsa_circ_0000437 promotes pathogenesis of gastric cancer and lymph node metastasis.
  17. Immunoglobulin superfamily 9 (IGSF9) is trans-activated by p53, inhibits breast cancer metastasis via FAK.
  18. MEX3A impairs DNA mismatch repair signaling and mediates acquired temozolomide resistance in glioblastoma.
  19. RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer.
  20. A biomarker of response to therapy in metastatic BRAFV600E colorectal cancers.
  21. Adipocyte mesenchymal transition contributes to mammary tumor progression.
  22. METTL1-mediated m7G tRNA modification promotes lenvatinib resistance in hepatocellular carcinoma.
  23. Can 3D bioprinting solve the mystery of senescence in cancer therapy?
  24. HDAC5 loss enhances phospholipid-derived arachidonic acid generation and confers sensitivity to cPLA2 inhibition in pancreatic cancer.
  25. Inhibition of UBA6 by inosine augments tumour immunogenicity and responses.
  26. Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2+ breast cancer by ceramide-loaded nanoparticles.
  27. PSMG2-controlled proteasome-autophagy balance mediates the tolerance for MEK-targeted therapy in triple-negative breast cancer.
  28. The roles of intratumour heterogeneity in the biology and treatment of pancreatic ductal adenocarcinoma.
  29. APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas.
  30. Postoperative plasmacytoid dendritic cells secrete IFN-α to promote recruitment of myeloid-derived suppressor cells and drive hepatocellular carcinoma recurrence.
  31. Adjuvant checkpoint blockade following complete local therapy for melanoma metastases.
  32. CDK14 inhibition reduces mammary stem cell activity and suppresses triple negative breast cancer progression.
  33. SerpinB3 drives cancer stem cell survival in glioblastoma.
  34. Space Is the Place: Mapping the Cell-Cell Interactions That Predict Immunotherapy Responses in Melanoma.
  35. Neutrophil-mediated fibroblast-tumor cell IL-6/STAT-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: a hybrid clinical-preclinical study.
  1. Nat Cancer. 2022 Sep 14.
    A dormancy mechanism limits metastasis of early spreading cancer cells.
      
    DOI:  https://doi.org/10.1038/s43018-022-00425-7
  2. Cancer Discov. 2022 Sep 13. pii: CD-22-0236. [Epub ahead of print]
    Cell Competition Shapes Metastatic Latency and Relapse.
    Kangsan Kim, Huocong Huang, Pravat Kumar Parida, Lan He, Mauricio Marquez-Palencia, Tanner C Reese, Payal Kapur, James Brugarolas, Rolf A Brekken, Srinivas Malladi.
      Cell competition, a fitness sensing process is essential for tissue homeostasis. Employing cancer metastatic latency models, we show that cell competition results in displacement of latent metastatic (Lat-M) cells from the primary tumor. Lat-M cells resist anoikis and survive as residual metastatic disease. Remodelled extracellular matrix facilitates Lat-M cell displacement and survival in circulation. Disrupting cell competition dynamics by depleting SPARC reduced displacement from orthotopic tumors and attenuated metastases. In contrast, depletion of SPARC post-extravasation in lung resident Lat-M cells increased metastatic outgrowth. Furthermore, multi-regional transcriptomic analyses of matched primary tumors and metachronous metastases from kidney cancer patients identified tumor subclones with latent metastatic traits. Kidney cancer enriched for these latent metastatic traits had rapid onset of metachronous metastases and significantly reduced disease-free survival. Thus, an unexpected consequence of cell competition is displacement of cells with latent metastatic potential, thereby shaping metastatic latency and relapse.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0236
  3. Nat Commun. 2022 Sep 15. 13(1): 5345
    Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.
    Thomas C Westbrook, Xiangnan Guan, Eva Rodansky, Diana Flores, Chia Jen Liu, Aaron M Udager, Radhika A Patel, Michael C Haffner, Ya-Mei Hu, Duanchen Sun, Tomasz M Beer, Adam Foye, Rahul Aggarwal, David A Quigley, Jack F Youngren, Charles J Ryan, Martin Gleave, Yuzhuo Wang, Jiaoti Huang, Ilsa Coleman, Colm Morrissey, Peter S Nelson, Christopher P Evans, Primo Lara, Robert E Reiter, Owen Witte, Matthew Rettig, Christopher K Wong, Alana S Weinstein, Vlado Uzunangelov, Josh M Stuart, George V Thomas, Felix Y Feng, Eric J Small, Joel A Yates, Zheng Xia, Joshi J Alumkal.
      The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.
    DOI:  https://doi.org/10.1038/s41467-022-32701-6
  4. Cancer Res. 2022 Sep 16. pii: CAN-21-3214. [Epub ahead of print]
    Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis.
    Aria Vaishnavi, Joseph Juan, Maebh Jacob, Christopher Stehn, Eric E Gardner, Michael T Scherzer, Sophia Schuman, J Edward van Veen, Brandon Murphy, Christopher S Hackett, Adam J Dupuy, Steve A Chmura, Louise van der Weyden, Justin Y Newberg, Annie Liu, Karen Mann, Alistair G Rust, William A Weiss, Conan G Kinsey, David J Adams, Allie Grossmann, Michael B Mann, Martin McMahon.
      Mutationally-activated BRAF is detected in ~7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we employed Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Amongst the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a putative tumor suppressor. Silencing of RBMS3 via CRISPR/Cas9 gene editing promoted growth of BRAFV600E lung organoids and promoted development of malignant lung cancers with a distinct micropapillary architecture in BRAFV600E and EGFRL858R GEM models. BRAFV600E/RBMS3Null lung tumors displayed elevated expression Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, suggesting that RBMS3 silencing elevates signaling through the WNT/β-catenin signaling axis. Although RBMS3 silencing rendered BRAFV600E-driven lung tumors resistant to the effects of dabrafenib plus trametinib, the tumors were sensitive to inhibition of Porcupine, an acyltransferase of WNT ligands necessary for their secretion. Analysis of TCGA patient samples revealed that chromosome 3P24, which harbors RBMS3, is frequently lost in NSCLC and correlates with poor prognosis. Collectively, these data reveal the role of RBMS3 as a lung cancer suppressor and suggest RBMS3 silencing may contribute to malignant progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3214
  5. Cancer Cell. 2022 Sep 12. pii: S1535-6108(22)00384-1. [Epub ahead of print]40(9): 905-907
    Targeting lineage plasticity overcomes chemoresistance.
    Seishi Ogawa.
      In this issue of Cancer Cell, Wang et al. reveal that chemoresistant muscle-invasive bladder cancer is associated with partial squamous differentiation. Targeting of Cathepsin H overcomes this chemotherapy-induced semi-squamatization and promotes terminal squamous differentiation and tumor suppression.
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.020
  6. Cancer Res. 2022 Sep 16. pii: CAN-22-1203. [Epub ahead of print]
    MEX3C-mediated decay of SOCS3 mRNA promotes JAK2/STAT3 signaling to facilitate metastasis in hepatocellular carcinoma.
    Yunyun Xiao, Yue Li, Dongni Shi, Xiaoqing Wang, Shuqin Dai, Muwen Yang, Lingzhi Kong, Boyu Chen, Xinjian Huang, Chuyong Lin, Wenting Liao, Benke Xu, Xin Chen, Lishuai Wang, Xiangfu Chen, Ying Ouyang, Guozhen Liu, Heping Li, Libing Song.
      Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)-mediated post-transcriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3'UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide (ASO) significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1203
  7. Cancer Discov. 2022 Sep 15. pii: CD-21-0865. [Epub ahead of print]
    Loss of epigenetic regulation disrupts lineage integrity, induces aberrant alveogenesis and promotes breast cancer.
    Ellen Langille, Khalid N Al-Zahrani, Zhibo Ma, Minggao Liang, Liis Uuskula-Reimand, Roderic Espin, Katie Teng, Ahmad Malik, Helga Bergholtz, Samah El Ghamrasni, Somaieh Afiuni-Zadeh, Ricky Tsai, Sana Alvi, Andrew Elia, YiQing Lu, Robin H Oh, Katelyn J Kozma, Daniel Trcka, Masahiro Narimatsu, Jeff C Liu, Thomas Nguyen, Seda Barutcu, Sampath K Loganathan, Rod Bremner, Gary D Bader, Sean E Egan, David W Cescon, Therese Sorlie, Jeffrey L Wrana, Hartland W Jackson, Michael D Wilson, Agnieszka K Witkiewicz, Erik S Knudsen, Miguel Angel Pujana, Geoffrey M Wahl, Daniel Schramek.
      Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for Precision Medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent 'long-tail' breast cancer genes, which revealed epigenetic regulation as a major tumor suppressive mechanism. We report that components of the BAP1 and the COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1 and ASXL1/2 ("EpiDrivers"), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of PIK3CAH1047R and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDrivers mutations are found in ~39% of human breast cancers and ~50% of ductal-carcinoma-in-situ express casein suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0865
  8. Cancer Cell. 2022 Sep 02. pii: S1535-6108(22)00391-9. [Epub ahead of print]
    Metabolic regulation of Cathepsin B in tumor macrophages drives their pro-metastatic function.
    Romana Vidergar, Subhra K Biswas.
      Tumor macrophages possess tumor-promoting functions, but the mechanism regulating such functions is poorly understood. Providing new insight into such mechanism, Shi et al. in this issue of Cancer Cell identify how metabolic regulation of Cathepsin B and its O-GlcNAcylation by lysosomal O-GlcNAc transferase (OGT) in macrophages drives pro-metastatic function.
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.023
  9. Nat Rev Drug Discov. 2022 Sep 14.
    PKN3: a target in cancer metastasis.
    Louisa Temme, Tuomo Laitinen, Christopher R M Asquith.
      
    DOI:  https://doi.org/10.1038/d41573-022-00154-7
  10. Cancer Cell. 2022 Sep 12. pii: S1535-6108(22)00382-8. [Epub ahead of print]40(9): 908-910
    Getting a handle on KRAS inhibitor resistance with hapten-mediated anti-tumor immunity.
    William A Freed-Pastor, Andrew J Aguirre.
      Covalent inhibitors of oncogenic KRASG12C have demonstrated impressive clinical responses; however, therapeutic resistance has been commonly observed. In this issue, Zhang and colleagues demonstrate that small molecule KRASG12C inhibitors can generate haptenated major histocompatibility complex (MHC) class I:peptide complexes, which represent attractive targets for immune-based therapies to combat pharmacologic resistance.
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.018
  11. Cancer Cell. 2022 Sep 12. pii: S1535-6108(22)00374-9. [Epub ahead of print]40(9): 1044-1059.e8
    Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer.
    Manli Wang, Xuelan Chen, Ping Tan, Yiyun Wang, Xiangyu Pan, Tianhai Lin, Yong Jiang, Bo Wang, Huan Xu, Yuying Wang, Yucen Yang, Jian Wang, Lei Zhao, Jiapeng Zhang, Ailing Zhong, Yiman Peng, Jiajia Du, Qi Zhang, Jianan Zheng, Jingyao Chen, Siqi Dai, Feifei Na, Zhenghao Lu, Jiaming Liu, Xiaonan Zheng, Lu Yang, Peng Zhang, Ping Han, Qiyong Gong, Qian Zhong, Kai Xiao, Hanshuo Yang, Hongxin Deng, Yinglan Zhao, Hubing Shi, Jianghong Man, Maling Gou, Chengjian Zhao, Lunzhi Dai, Zhihong Xue, Lu Chen, Yuan Wang, Musheng Zeng, Canhua Huang, Qiang Wei, Yuquan Wei, Yu Liu, Chong Chen.
      Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.
    Keywords:  E64; MIBC; TNF pathway; acquired chemoresistance; cathepsin H; differentiation therapy; lineage plasticity; pyroptosis; semi-squamatization
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.010
  12. Cancer Res. 2022 Sep 14. pii: CAN-22-1170. [Epub ahead of print]
    WNT5A-RHOA signaling is a driver of tumorigenesis and represents a therapeutically actionable vulnerability in small cell lung cancer.
    Kee-Beom Kim, Dong-Wook Kim, Youngchul Kim, Jun Tang, Nicole Kirk, Yongyu Gan, Bongjun Kim, Bingliang Fang, Jae-Ll Park, Yi Zheng, Kwon-Sik Park.
      WNT signaling represents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers. Here, we characterize WNT pathway activity in small cell lung cancer (SCLC) and determine the functional role of WNT signaling using genetically engineered mouse models GEMMs). β-catenin, a master mediator of canonical WNT signaling, was dispensable for SCLC development, and its transcriptional program was largely silenced during tumor development. Conversely, WNT5A, a ligand for β-catenin-independent noncanonical WNT pathways, promoted neoplastic transformation and SCLC cell proliferation, while WNT5A deficiency inhibited SCLC development. Loss of p130 in SCLC cells induced expression of WNT5A, which selectively increased Rhoa transcription and activated RHOA protein to drive SCLC. Rhoa knockout suppressed SCLC development in vivo, and chemical perturbation of RHOA selectively inhibited SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A-RHOA axis in SCLC, providing critical insights for the development of novel therapeutic strategies for this recalcitrant cancer. This study also sheds light on the heterogeneity of WNT signaling in cancer and the molecular determinants of its cell-type specificity.  .
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1170
  13. Phys Rev Lett. 2022 Sep 02. 129(10): 108101
    Phenomenological Approach to Cancer Cell Persistence.
    David A Kessler, Herbert Levine.
      Drug persistence is a phenomenon by which a small percentage of cancer cells survive the presentation of targeted therapy by transitioning to a quiescent state. Eventually some of these persister cells can transition back to an active growing state and give rise to resistant tumors. Here we introduce a quantitative genetics approach to drug-exposed populations of cancer cells in order to interpret recent experimental data regarding inheritance of persister probability. Our results indicate that alternating periods of drug treatment and drug removal may not be an effective strategy for eliminating persisters.
    DOI:  https://doi.org/10.1103/PhysRevLett.129.108101
  14. J Immunother Cancer. 2022 Sep;pii: e004884. [Epub ahead of print]10(9):
    Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites.
    Jordan W Conway, Robert V Rawson, Serigne Lo, Tasnia Ahmed, Ismael A Vergara, Tuba N Gide, Grace Heloise Attrill, Matteo S Carlino, Robyn P M Saw, John F Thompson, Andrew J Spillane, Kerwin F Shannon, Brindha Shivalingam, Alexander Maxwell Menzies, James S Wilmott, Georgina V Long, Richard A Scolyer, Ines Pires da Silva.
      BACKGROUND: The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases.METHODS: We analyzed OS in 1924 systemic treatment-naïve patients with AJCC (American Joint Committee on Cancer) stage IV melanoma with a solitary site of organ metastasis. In an independent cohort we analyzed and compared immune cell densities, subpopulations and spatial distribution in tissue from liver, lung, brain, LN or subcut sites from 130 patients with stage IV melanoma.
    RESULTS: Patients with only liver, brain or bone metastases had shorter OS compared to those with lung, LN or subcutaneous and soft tissue metastases. Liver and brain metastases had significantly lower T-cell infiltration than lung (p=0.0116 and p=0.0252, respectively) and LN metastases (p=0.0116 and p=0.0252, respectively). T cells were further away from melanoma cells in liver than lung metastases (p=0.0335). Liver metastases displayed unique T-cell profiles, with a significantly lower proportion of programmed cell death protein-1+ T cells compared to all other anatomical sites (p<0.05), and a higher proportion of TIM-3+ T cells compared to LN (p=0.0004), subcut (p=0.0082) and brain (p=0.0128) metastases. Brain metastases had a lower macrophage density than subcut (p=0.0105), liver (p=0.0095) and lung (p<0.0001) metastases. Lung metastases had the highest proportion of programmed death ligand-1+ macrophages of the total macrophage population, significantly higher than brain (p<0.0001) and liver metastases (p=0.0392).
    CONCLUSIONS: Liver and brain melanoma metastases have a significantly reduced immune infiltrate than lung, subcut and LN metastases, which may account for poorer prognosis and reduced immunotherapy response rates in patients with liver or brain metastases. Increased TIM-3 expression in liver metastases suggests TIM-3 inhibitor therapy as a potential therapeutic opportunity to improve patient outcomes.
    Keywords:  Immunohistochemistry; Macrophages; Melanoma; T-Lymphocytes; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2022-004884
  15. Ann Oncol. 2022 Sep 08. pii: S0923-7534(22)04141-2. [Epub ahead of print]
    The Clinical Landscape of Cell-Free DNA Alterations in 1,671 Patients with Advanced Biliary Tract Cancer.
    Jacob E Berchuck, Francesco Facchinetti, Daniel F DiToro, Islam Baiev, Umair Majeed, Stephanie Reyes, Christopher Chen, Karen Zhang, Reya Sharman, Pedro Luiz Serrano Uson Junior, Jordan Maurer, Rachna T Shroff, Colin C Pritchard, Meng-Ju Wu, Daniel V T Catenacci, Milind Javle, Luc Friboulet, Antoine Hollebecque, Nabeel Bardeesy, Andrew X Zhu, Jochen K Lennerz, Benjamin Tan, Mitesh Borad, Aparna R Parikh, Lesli A Kiedrowski, Robin Kate Kelley, Kabir Mody, Dejan Juric, Lipika Goyal.
      BACKGROUND: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology.PATIENTS AND METHODS: We analyzed next-generation sequencing data of 2,068 cfDNA samples from 1,671 patients with advanced BTC generated with Guardant360. We performed clinical annotation on a multi-institutional subset (n=225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes.
    RESULTS: Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. FGFR2 fusions, IDH1 mutations, and BRAF V600E were clonal in majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%).
    CONCLUSIONS: These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.
    Keywords:  Biliary tract cancer; Cell-free DNA; Cholangiocarcinoma; Liquid Biopsy
    DOI:  https://doi.org/10.1016/j.annonc.2022.09.150
  16. Oncogene. 2022 Sep 15.
    Hsa_circ_0000437 promotes pathogenesis of gastric cancer and lymph node metastasis.
    Xianjuan Shen, Shan Kong, Shuo Ma, Lei Shen, Ming Zheng, Shiyi Qin, Jing Qi, Qiuhong Wang, Xiaopeng Cui, Shaoqing Ju.
      Cellular communication between gastric cancer (GC) cells with different metastatic potentials and microenvironments and resultant cancer progression is not fully understood. Circular RNAs (circRNAs) and exosomal circRNAs are known to play extremely important regulatory roles in GC occurrence and progression. Here, we revealed significant differences in coronin-like actin-binding protein 1C (CORO1C) derived circRNA hsa_circ_0000437 between GC and para-cancer tissues. Hsa_circ_0000437 regulated GC cell proliferation, invasion, migration and apoptosis by targeting Ser/Arg-rich splicing factor 3 (SRSF3) and inhibiting programmed cell death 4 (PDCD4). The ectopic expression of hsa_circ_0000437 dramatically promoted tumor growth in nude mice in vivo. Furthermore, both gain-of-function and loss-of-function experiments demonstrated that hsa_circ_0000437 promoted human lymphatic endothelial cells (HLECs) invasion, migration, and tube formation in vitro and also promoted lymphangiogenesis and lymph node metastasis (LNM) in popliteal LNM model in vivo, when it was enriched in GC-secreted exosomes and transferred into HLECs. Mechanistically, exosomal hsa_circ_0000437 induced LNM via HSPA2-ERK signaling pathway independent of VEGF-C. Clinical data showed that exosomal hsa_circ_0000437 was enriched in the serum of GC patients, which was associated with LNM. In summary, these findings highlight the potential role of hsa_circ_0000437 as an outcome biomarker in GC patients with LNM, which may provide a novel target for GC therapy.
    DOI:  https://doi.org/10.1038/s41388-022-02449-w
  17. Oncogene. 2022 Sep 10.
    Immunoglobulin superfamily 9 (IGSF9) is trans-activated by p53, inhibits breast cancer metastasis via FAK.
    Yaohua Li, Yiran Deng, Yannan Zhao, Wei Zhang, Si Zhang, Li Zhang, Biyun Wang, Yingying Xu, She Chen.
      Metastasis of breast cancer represents the major reason for its poor prognosis, leading to high mortality. In breast cancer, a tumor suppressor gene TP53 is commonly mutated. TP53 mutation leads to an altered expression of various genes, an event that is associated with aggressive tumor and is a strong independent marker for survival. In this study, we identified a novel p53 target gene, immunoglobulin superfamily 9 (IGSF9). IGSF9 is generally down-regulated in breast cancer tissues. Loss of IGSF9 is associated with frequent metastasis and poor prognosis of breast cancer patients. Wild-type p53, but not R175H mutant, trans-activates the transcription of IGSF9 via binding to its promoter (-137 to -131 bp), inhibits epithelial-mesenchymal transition (EMT), consequently the inhibition of breast cancer cells migration and invasion. IGSF9 interacts with focal adhesion kinase (FAK) and inhibits FAK/AKT signaling activity. PND1186, FAK inhibitor, inhibits breast cancer metastasis induced by IGSF9 knockdown in vitro and in vivo. Taken together, IGSF9 is trans-activated by p53 and inhibits breast cancer metastasis by modulating FAK/AKT signaling pathway. IGSF9 could serve as a prognostic marker and potential therapeutic target for breast cancer.
    DOI:  https://doi.org/10.1038/s41388-022-02459-8
  18. Cancer Res. 2022 Sep 16. pii: CAN-22-2036. [Epub ahead of print]
    MEX3A impairs DNA mismatch repair signaling and mediates acquired temozolomide resistance in glioblastoma.
    Tian Gan, Yan Wang, Manyi Xie, Qiang Wang, Saisai Zhao, Peng Wang, Qinyu Shi, Xuanchen Qian, Faan Miao, Zhigang Shen, Er Nie.
      MutS protein homolog 2 (MSH2) is a key element involved in the DNA mismatch repair system, which is responsible for recognizing and repairing mispaired bases. Simultaneously, MSH2 identifies DNA adducts induced by temozolomide (TMZ) and triggers apoptosis and autophagy in tumor cells. Previous work has revealed that reduced MSH2 expression is often observed in glioblastoma (GBM) patients who relapse after chemotherapy. Elucidation of the mechanism behind TMZ-mediated reduction of MSH2 could help improve GBM treatment. Here, we report significant upregulation of Mex-3 RNA binding family member A (MEX3A) in GBM tissues and cell lines following TMZ treatment. MEX3A bound to the MEX-3 recognition element (MRE) of MSH2 mRNA, which in turn recruited CCR4-NOT complexes to target MSH2 mRNA for deadenylation and degradation. In addition, ectopic expression of MEX3A significantly decreased cellular DNA mismatch repair activities and reduced the chemosensitivity of GBM cells via downregulation of MSH2, while depletion of MEX3A sensitized GBM cells to TMZ. In MGMT-deficient GBM patients, MEX3A expression correlated with MSH2 levels, and high MEX3A expression was associated with poor prognosis. Overall, these findings reveal a potential mechanism by which MSH2 expression is reduced in post-TMZ recurrent GBM.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2036
  19. Nat Med. 2022 Sep 12.
    RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer.
    Elena Elez, Javier Ros, Jose Fernández, Guillermo Villacampa, Ana Belén Moreno-Cárdenas, Carlota Arenillas, Kinga Bernatowicz, Raquel Comas, Shanshan Li, David Philip Kodack, Roberta Fasani, Ariadna Garcia, Javier Gonzalo-Ruiz, Alejandro Piris-Gimenez, Paolo Nuciforo, Grainne Kerr, Rossana Intini, Aldo Montagna, Marco Maria Germani, Giovanni Randon, Ana Vivancos, Ron Smits, Diana Graus, Raquel Perez-Lopez, Chiara Cremolini, Sara Lonardi, Filippo Pietrantonio, Rodrigo Dienstmann, Josep Tabernero, Rodrigo A Toledo.
      Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12-0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10-0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.
    DOI:  https://doi.org/10.1038/s41591-022-01976-z
  20. Nat Med. 2022 Sep 14.
    A biomarker of response to therapy in metastatic BRAFV600E colorectal cancers.
      
    DOI:  https://doi.org/10.1038/s41591-022-01988-9
  21. Cell Rep. 2022 Sep 13. pii: S2211-1247(22)01194-9. [Epub ahead of print]40(11): 111362
    Adipocyte mesenchymal transition contributes to mammary tumor progression.
    Qingzhang Zhu, Yi Zhu, Chelsea Hepler, Qianbin Zhang, Jiyoung Park, Christy Gliniak, Gervaise H Henry, Clair Crewe, Dawei Bu, Zhuzhen Zhang, Shangang Zhao, Thomas Morley, Na Li, Dae-Seok Kim, Douglas Strand, Yingfeng Deng, Jacob J Robino, Oleg Varlamov, Ruth Gordillo, Mikhail G Kolonin, Christine M Kusminski, Rana K Gupta, Philipp E Scherer.
      Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment.
    Keywords:  CP: Cancer; CP: Metabolism; adipocyte; breast cancer; de-differentiation; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2022.111362
  22. Cancer Res. 2022 Sep 14. pii: CAN-22-0963. [Epub ahead of print]
    METTL1-mediated m7G tRNA modification promotes lenvatinib resistance in hepatocellular carcinoma.
    Manling Huang, Jianting Long, Zhijia Yao, Yi Zhao, Yutong Zhao, Junbin Liao, Kai Lei, Han Xiao, Zihao Dai, Sui Peng, Shuibin Lin, Lixia Xu, Ming Kuang.
      The tyrosine kinase inhibitor lenvatinib is a first-line drug for treating patients with advanced hepatocellular carcinoma (HCC). However, its efficacy is severely hampered by drug resistance. Insights into the molecular mechanisms underlying lenvatinib resistance could provide new strategies to improve and prolong responses. Here, we performed unbiased proteomic screening of parental and lenvatinib-resistant HCC cells and discovered that METTL1 and WDR4, the two key components of the tRNA m7G methyltransferase complex, were dramatically upregulated in lenvatinib-resistant cells. METTL1 knockdown overrode resistance by impairing the proliferation capacity of HCC cells and promoting apoptosis under lenvatinib treatment. In addition, overexpression of wild-type METTL1 but not its catalytic dead mutant induced lenvatinib resistance. Animal experiments including hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models further demonstrated the critical function of METTL1/WDR4-mediated m7G tRNA modification in promoting lenvatinib resistance in vivo. Mechanistically, METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m7G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0963
  23. Ageing Res Rev. 2022 Sep 12. pii: S1568-1637(22)00174-X. [Epub ahead of print]81 101732
    Can 3D bioprinting solve the mystery of senescence in cancer therapy?
    Sofian Al Shboul, Valerie J DeLuca, Yazan Al Dweiri, Tareq Saleh.
      Tumor dormancy leading to cancer relapse is still a poorly understood mechanism. Several cell states such as quiescence and diapause can explain the persistence of tumor cells in a dormant state, but the potential role of tumor cell senescence has been met with hesitance given the historical understanding of the senescent growth arrest as irreversible. However, recent evidence has suggested that senescence might contribute to dormancy and relapse, although its exact role is not fully developed. This limited understanding is largely due to the paucity of reliable study models. The current 2D cell modeling is overly simplistic and lacks the appropriate representation of the interactions between tumor cells (senescent or non-senescent) and the other cell types within the tumor microenvironment (TME), as well as with the extracellular matrix (ECM). 3D cell culture models, including 3D bioprinting techniques, offer a promising approach to better recapitulate the native cancer microenvironment and would significantly improve our understanding of cancer biology and cellular response to treatment, particularly Therapy-Induced Senescence (TIS), and its contribution to tumor dormancy and cancer recurrence. Fabricating a novel 3D bioprinted model offers excellent opportunities to investigate both the role of TIS in tumor dormancy and the utility of senolytics (drugs that selectively eliminate senescent cells) in targeting dormant cancer cells and mitigating the risk for resurgence. In this review, we discuss literature on the possible contribution of TIS in tumor dormancy, provide examples on the current 3D models of senescence, and propose a novel 3D model to investigate the ultimate role of TIS in mediating overall response to therapy.
    Keywords:  3D bioprinting; Dormancy; Recurrence; Senescence; Senolytic; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.arr.2022.101732
  24. Cancer Res. 2022 Sep 14. pii: CAN-21-4362. [Epub ahead of print]
    HDAC5 loss enhances phospholipid-derived arachidonic acid generation and confers sensitivity to cPLA2 inhibition in pancreatic cancer.
    Penglin Pan, Gengdu Qin, Bo Wang, Haixin Yu, Jie Chen, Jiaying Liu, Kaijian Bing, Jian Shen, Dianyun Ren, Yuhan Zhao, Wentao Xia, Hui Li, Heshui Wu, Yingke Zhou.
      HDAC5 is a class IIa histone deacetylase member that is downregulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with unfavorable prognosis. In this study, assessment of The Cancer Genome Atlas (TGCA) pancreatic adenocarcinoma dataset revealed that expression of HDAC5 correlates negatively with arachidonic acid (AA) metabolism, which has been implicated in inflammatory responses and cancer progression. Non-targeted metabolomics analysis revealed that HDAC5 knockdown resulted in a significant increase in AA and its downstream metabolites, such as eicosanoids and prostaglandins. HDAC5 negatively regulated the expression of the gene encoding calcium-dependent phospholipase A2 (cPLA2), the key enzyme in the production of AA from phospholipids. Mechanistically, HDAC5 repressed cPLA2 expression via deacetylation of GATA1. HDAC5 knockdown in cancer cells enhanced sensitivity to genetic or pharmacological inhibition of cPLA2 in vitro and in vivo. Fatty acid supplementation in the diet reversed the sensitivity of HDAC5 deficient tumors to cPLA2 inhibition. These data indicate that HDAC5 loss in pancreatic cancer results in the hyperacetylation of GATA1, enabling the upregulation of cPLA2, which contributes to overproduction of AA. Dietary management plus cPLA2-targeted therapy could serve as a viable strategy for treating HDAC5 deficient pancreatic cancer patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-4362
  25. Nat Commun. 2022 Sep 15. 13(1): 5413
    Inhibition of UBA6 by inosine augments tumour immunogenicity and responses.
    Lei Zhang, Li Jiang, Liang Yu, Qin Li, Xiangjun Tian, Jingquan He, Ling Zeng, Yuqin Yang, Chaoran Wang, Yuhan Wei, Xiaoyue Jiang, Jing Li, Xiaolu Ge, Qisheng Gu, Jikun Li, Di Wu, Anthony J Sadler, Di Yu, Dakang Xu, Yue Gao, Xiangliang Yuan, Baokun He.
      Anti-cancer immunity and response to immune therapy is influenced by the metabolic states of the tumours. Immune checkpoint blockade therapy (ICB) is known to involve metabolic adaptation, however, the mechanism is not fully known. Here we show, by metabolic profiling of plasma samples from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and hence generating an immunologically hotter microenvironment. We find that inosine directly inhibits UBA6 in tumour cells, and lower level of UBA6 makes the tumour more immunogenic and this is reflected in favourable outcome following ICB therapy in human melanomas. Transplanted mouse melanoma and breast cancer cells with genetic ablation of Uba6 show higher sensitivity to ICB than wild type tumours. Thus, we provide evidence of an inosine-regulated UBA6-dependent pathway governing tumour-intrinsic immunogenicity and hence sensitivity to immune checkpoint inhibition, which might provide targets to overcome ICB resistance.
    DOI:  https://doi.org/10.1038/s41467-022-33116-z
  26. Proc Natl Acad Sci U S A. 2022 Sep 20. 119(38): e2205454119
    Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2+ breast cancer by ceramide-loaded nanoparticles.
    Sandeep Kumar, Subhasis Das, Jingjing Sun, Yixian Huang, Sunil Kumar Singh, Piush Srivastava, Gautam Sondarva, Rakesh Sathish Nair, Navin Viswakarma, Balaji B Ganesh, Lei Duan, Carl G Maki, Kent Hoskins, Oana Danciu, Basabi Rana, Song Li, Ajay Rana.
      Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but often patients develop acquired resistance. Although other agents are in clinical use to treat trastuzumab-resistant (TR) breast cancer; still, the patients develop recurrent metastatic disease. One of the primary mechanisms of acquired resistance is the shedding/loss of the HER2 extracellular domain, where trastuzumab binds. We envisioned any new agent acting downstream of the HER2 should overcome trastuzumab resistance. The mixed lineage kinase 3 (MLK3) activation by trastuzumab is necessary for promoting cell death in HER2+ breast cancer. We designed nanoparticles loaded with MLK3 agonist ceramide (PPP-CNP) and tested their efficacy in sensitizing TR cell lines, patient-derived organoids, and patient-derived xenograft (PDX). The PPP-CNP activated MLK3, its downstream JNK kinase activity, and down-regulated AKT pathway signaling in TR cell lines and PDX. The activation of MLK3 and down-regulation of AKT signaling by PPP-CNP induced cell death and inhibited cellular proliferation in TR cells and PDX. The apoptosis in TR cells was dependent on increased CD70 protein expression and caspase-9 and caspase-3 activities by PPP-CNP. The PPP-CNP treatment alike increased the expression of CD70, CD27, cleaved caspase-9, and caspase-3 with a concurrent tumor burden reduction of TR PDX. Moreover, the expressions of CD70 and ceramide levels were lower in TR than sensitive HER2+ human breast tumors. Our in vitro and preclinical animal models suggest that activating the MLK3-CD70 axis by the PPP-CNP could sensitize/overcome trastuzumab resistance in HER2+ breast cancer.
    Keywords:  CD70; MLK3; apoptosis; breast cancer; trastuzumab resistance
    DOI:  https://doi.org/10.1073/pnas.2205454119
  27. Cell Rep Med. 2022 Sep 07. pii: S2666-3791(22)00290-7. [Epub ahead of print] 100741
    PSMG2-controlled proteasome-autophagy balance mediates the tolerance for MEK-targeted therapy in triple-negative breast cancer.
    Xueyan Wang, Jing Yu, Xiaowei Liu, Dan Luo, Yanchu Li, Linlin Song, Xian Jiang, Xiaomeng Yin, Yan Wang, Li Chai, Ting Luo, Jing Jing, Hubing Shi.
      Although the MAPK pathway is aberrantly activated in triple-negative breast cancers (TNBCs), the clinical outcome of MEK-targeted therapy is still poor. Through a genome-wide CRISPR-Cas9 library screening, we find that inhibition of PSMG2 sensitizes TNBC cells BT549 and MB468 to the MEK inhibitor AZD6244. Mechanistically, PSMG2 knockdown impairs proteasome function, which in turn activates autophagy-mediated PDPK1 degradation. The PDPK1 degradation significantly enhances AZD6244-induced tumor cell growth inhibition by interrupting the negative feedback signals toward the AKT pathway. Consistently, co-targeting proteasomes and MEK with inhibitors synergistically suppresses tumor cell growth. The autophagy inhibitor chloroquine partially relieves the PDPK1 degradation and reverses the growth inhibition induced by combinatorial inhibition of MEK and proteasome. The combination regimen with the proteasome inhibitor MG132 plus AZD6244 synergistically inhibits tumor growth in a 4T1 xenograft mouse model. In summary, our study not only unravels the mechanism of MEK inhibitor resistance but also provides a combinatorial therapeutic strategy for TNBC in clinics.
    Keywords:  AKT pathway; CRISPR-Cas9; MAPK pathway; PDPK1; PSMG2; autophagy; proteasome; resistance; targeted therapy; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.xcrm.2022.100741
  28. Oncogene. 2022 Sep 10.
    The roles of intratumour heterogeneity in the biology and treatment of pancreatic ductal adenocarcinoma.
    Theodore Evan, Victoria Min-Yi Wang, Axel Behrens.
      Intratumour heterogeneity (ITH) has become an important focus of cancer research in recent years. ITH describes the cellular variation that enables tumour evolution, including tumour progression, metastasis and resistance to treatment. The selection and expansion of genetically distinct treatment-resistant cancer cell clones provides one explanation for treatment failure. However, tumour cell variation need not be genetically encoded. In pancreatic ductal adenocarcinoma (PDAC) in particular, the complex tumour microenvironment as well as crosstalk between tumour and stromal cells result in exceptionally variable tumour cell phenotypes that are also highly adaptable. In this review we discuss four different types of phenotypic heterogeneity within PDAC, from morphological to metabolic heterogeneity. We suggest that these different types of ITH are not independent, but, rather, can inform one another. Lastly, we highlight recent findings that suggest how therapeutic efforts may halt PDAC progression by constraining cellular heterogeneity.
    DOI:  https://doi.org/10.1038/s41388-022-02448-x
  29. Ann Oncol. 2022 Sep 08. pii: S0923-7534(22)04142-4. [Epub ahead of print]
    APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas.
    P Selenica, A Marra, N J Choudhury, A Gazzo, C J Falcon, J Patel, X Pei, Y Zhu, C K Y Ng, M Curry, G Heller, Y-K Zhang, M F Berger, M Ladanyi, C M Rudin, S Chandarlapaty, C M Lovly, J S Reis-Filho, H A Yu.
      BACKGROUND: Studies of targeted therapy resistance in lung cancer have primarily focused on single gene alterations. Based on prior work implicating APOBEC mutagenesis in histological transformation of EGFR-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies.PATIENTS AND METHODS: APOBEC mutational signatures derived from an FDA-cleared multigene panel (MSK-IMPACT) using the SigMA algorithm were validated against the gold standard of mutational signatures derived from whole exome sequencing. Mutational signatures were decomposed in 3,276 unique lung adenocarcinomas, including 93 paired osimertinib-naïve and resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing (WGS) was performed on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large scale genomic alterations potentially contributing to osimertinib resistance.
    RESULTS: APOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET and ROS1; 25%) compared to lung adenocarcinomas at large (20%, p<0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (p<0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC dominant mutational signature compared to osimertinib-naïve samples (28 vs.14% p=0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC dominant mutational signature (44% vs 23%, p<0.001). EGFR-mutant samples with APOBEC dominant signatures had enrichment of large scale-genomic rearrangements (p=0.01) and kataegis (p=0.03) in areas of APOBEC mutagenesis.
    CONCLUSIONS: APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.
    Keywords:  APOBEC; EGFR; acquired resistance; mutational signatures; osimertinib; structural rearrangements; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1016/j.annonc.2022.09.151
  30. Cancer Res. 2022 Sep 14. pii: CAN-22-1199. [Epub ahead of print]
    Postoperative plasmacytoid dendritic cells secrete IFN-α to promote recruitment of myeloid-derived suppressor cells and drive hepatocellular carcinoma recurrence.
    Kwan Man, Li Pang, Oscar W H Yeung, Kevin T P Ng, Hui Liu, Jiye Zhu, Jiang Liu, Xinxiang Yang, Tao Ding, Wenqi Qiu, Yuewen Wang, T L Shirley Chiu, Zhiwei Chen, Chung Mau Lo.
      Patients with hepatocellular carcinoma (HCC) confront a high incidence of tumor recurrence after curative surgical resection. Hepatic ischemia-reperfusion injury (IRI) is the major consequence of surgical stress during hepatectomy. While it has been suggested that hepatic IRI-induced immunosuppression could contribute to tumor relapse after surgery, the underlying mechanisms have not been fully defined. Here, using a multiplex cytokine array, we found that levels of postoperative IFN-α serve as an independent risk factor for tumor recurrence in 100 HCC patients with curative hepatectomy. Plasmacytoid dendritic cells (pDCs), the major source of IFN-α, were activated after surgery and correlated with poor disease-free survival. Functionally, IFN-α was responsible for mobilization of myeloid-derived suppressor cells (MDSC) following hepatic IRI. Conditioned medium from IFN-α treated hepatocytes mediated the migration of MDSCs in vitro. Mechanistically, IFN-α upregulated IRF1 to promote hepatocyte expression of CX3CL1, which subsequently recruited CX3CR1+ monocytic MDSCs. Knockdown of Irf1 or Cx3cl1 in hepatocytes significantly inhibited the accumulation of monocytic MDSCs in vivo. Therapeutically, elimination of pDCs, IFN-α, or CX3CR1 could restore the tumor-killing activity of CD8+ T cells, hence limiting tumor growth and lung metastasis following hepatic IRI. Taken together, these data suggest that IFN-α-producing pDCs drive CX3CR1+ MDSC recruitment via hepatocyte IRF1/CX3CL1 signaling and lead to tumor recurrence after hepatectomy in HCC. Targeting pDCs and the IFN-α/CX3CL1/CX3CR1 axis could inhibit surgical-stress-induced HCC recurrence by attenuating postoperative immunosuppression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1199
  31. Lancet. 2022 Sep 09. pii: S0140-6736(22)01748-2. [Epub ahead of print]
    Adjuvant checkpoint blockade following complete local therapy for melanoma metastases.
    James W Smithy, Michael A Postow.
      
    DOI:  https://doi.org/10.1016/S0140-6736(22)01748-2
  32. Cell Rep. 2022 Sep 13. pii: S2211-1247(22)01159-7. [Epub ahead of print]40(11): 111331
    CDK14 inhibition reduces mammary stem cell activity and suppresses triple negative breast cancer progression.
    Mengna Zhang, Lingxian Zhang, Ajun Geng, Xiao Li, Yu Zhou, Liming Xu, Yi Arial Zeng, Jinpeng Li, Cheguo Cai.
      The Wnt/β-catenin signaling pathway plays an important role in regulating mammary organogenesis and oncogenesis. However, therapeutic methods targeting the Wnt pathway against breast cancer have been limited. To address this challenge, we investigate the function of cyclin-dependent kinase 14 (CDK14), a member of the Wnt signaling pathway, in mammary development and breast cancer progression. We show that CDK14 is expressed in the mammary basal layer and elevated in triple negative breast cancer (TNBC). CDK14 knockdown reduces the colony-formation ability and regeneration capacity of mammary basal cells and inhibits the progression of murine MMTV-Wnt-1 basal-like mammary tumor. CDK14 knockdown or pharmacological inhibition by FMF-04-159-2 suppresses the progression and metastasis of TNBC. Mechanistically, CDK14 inhibition inhibits mammary regeneration and TNBC progression by attenuating Wnt/β-catenin signaling. These findings highlight the significance of CDK14 in mammary development and TNBC progression, shedding light on CDK14 as a promising therapeutic target for TNBC.
    Keywords:  CDK14; CP: Cancer; Wnt/β-catenin signal; mammary stem cell; triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.celrep.2022.111331
  33. Cell Rep. 2022 Sep 13. pii: S2211-1247(22)01176-7. [Epub ahead of print]40(11): 111348
    SerpinB3 drives cancer stem cell survival in glioblastoma.
    Adam Lauko, Josephine Volovetz, Soumya M Turaga, Defne Bayik, Daniel J Silver, Kelly Mitchell, Erin E Mulkearns-Hubert, Dionysios C Watson, Kiran Desai, Manav Midha, Jing Hao, Kathleen McCortney, Alicia Steffens, Ulhas Naik, Manmeet S Ahluwalia, Shideng Bao, Craig Horbinski, Jennifer S Yu, Justin D Lathia.
      Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a GBM CSC-specific survival mechanism involving a cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of GBM therapies against therapeutically resistant CSCs.
    Keywords:  CP: Cancer; SerpinB3; cancer stem cell; cathepsin L; glioblastoma; lysosomal-mediated cell death
    DOI:  https://doi.org/10.1016/j.celrep.2022.111348
  34. Cancer Res. 2022 Sep 16. 82(18): 3198-3200
    Space Is the Place: Mapping the Cell-Cell Interactions That Predict Immunotherapy Responses in Melanoma.
    Inna Smalley, Keiran S M Smalley.
      Although immune checkpoint inhibition (ICI) has revolutionized the treatment of advanced melanoma, reliable predictive biomarkers are still lacking. In this issue of Cancer Research, Antoranz and colleagues used RNA sequencing and multiplexed IHC to study the spatial immune landscape of pretreatment melanoma specimens from patients who either responded or did not respond to antiprogrammed death protein 1 (PD-1) therapy. The authors identified the spatial interaction between cytotoxic T cells and M1-like macrophages expressing PD-L1 at the tumor boundary as predictive of responses to immune checkpoint inhibition. These studies pave the way for the development of new spatial biomarkers to identify patients most likely to benefit from ICI therapy. See related article by Antoranz et al., p. 3275.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2192
  35. Elife. 2022 Sep 15. pii: e78921. [Epub ahead of print]11
    Neutrophil-mediated fibroblast-tumor cell IL-6/STAT-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: a hybrid clinical-preclinical study.
    Iago de Castro Silva, Anna Bianchi, Nilesh U Deshpande, Prateek Sharma, Siddharth Mehra, Vanessa Tonin Garrido, Shannon Jacqueline Saigh, Jonathan England, Peter Joel Hosein, Deukwoo Kwon, Nipun B Merchant, Jashodeep Datta.
      Background: Partial/complete pathologic response following neoadjuvant chemotherapy (NAC) in pancreatic cancer (PDAC) patients undergoing pancreatectomy is associated with improved survival. We sought to determine whether neutrophil-to-lymphocyte ratio (NLR) dynamics predict pathologic response following chemotherapy in PDAC, and if manipulating NLR impacts chemosensitivity in preclinical models and uncovers potential mechanistic underpinnings underlying these effects.Methods: Pathologic response in PDAC patients (n=94) undergoing NAC and pancreatectomy (7/2015-12/2019) was dichotomized as partial/complete or poor/absent. Bootstrap-validated multivariable models assessed associations between pre-chemotherapy NLR (%neutrophils÷%lymphocytes) or NLR dynamics during chemotherapy (ΔNLR=pre-surgery-pre-chemotherapy NLR) and pathologic response, disease-free survival (DFS), and overall survival (OS). To preclinically model effects of NLR attenuation on chemosensitivity, Ptf1aCre/+; KrasLSL-G12D/+;Tgfbr2flox/flox (PKT) mice and C57BL/6 mice orthotopically injected with KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx1Cre (KPC) cells were randomized to vehicle, gemcitabine/paclitaxel alone, and NLR-attenuating anti-Ly6G with/without gemcitabine/paclitaxel treatment.
    Results: In 94 PDAC patients undergoing NAC (median:4 months), pre-chemotherapy NLR (P<0.001) and ΔNLR attenuation during NAC (P=0.002) were independently associated with partial/complete pathologic response. An NLR score=pre-chemotherapy NLR+ΔNLR correlated with DFS (P=0.006) and OS (P=0.002). Upon preclinical modeling, combining NLR-attenuating anti-Ly6G treatment with gemcitabine/paclitaxel-compared with gemcitabine/paclitaxel or anti-Ly6G alone-not only significantly reduced tumor burden and metastatic outgrowth, but also augmented tumor-infiltrating CD107a+-degranulating CD8+ T-cells (P<0.01) while dampening inflammatory cancer-associated fibroblast (CAF) polarization (P=0.006) and chemoresistant IL-6/STAT-3 signaling in vivo. Neutrophil-derived IL-1β emerged as a novel mediator of stromal inflammation, inducing inflammatory CAF polarization and CAF-tumor cell IL-6/STAT-3 signaling in ex vivo co-cultures.
    Conclusions: Therapeutic strategies to mitigate neutrophil-CAF-tumor cell IL-1β/IL-6/STAT-3 signaling during NAC may improve pathologic responses and/or survival in PDAC.
    Funding: Supported by KL2 career development grant by Miami CTSI under NIH Award UL1TR002736, Stanley Glaser Foundation, American College of Surgeons Franklin Martin Career Development Award, and Association for Academic Surgery Joel J. Roslyn Faculty Award (to J. Datta); NIH R01 CA161976 (to N.B. Merchant); and NCI/NIH Award P30CA240139 (to J. Datta and N.B. Merchant).
    Keywords:  human; immunology; inflammation; medicine; mouse
    DOI:  https://doi.org/10.7554/eLife.78921
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