bims-tucedo 2021-12-19 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2021–12–19
28 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology

Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response.
Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer.
An in vivo CRISPR screen identifies stepwise genetic dependencies of metastatic progression.
Integrated Metabolic Profiling and Transcriptional Analysis Reveals Therapeutic Modalities for Targeting Rapidly Proliferating Breast Cancers.
How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer.
Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis.
The circular RNA circDLG1 promotes gastric cancer progression and anti-PD-1 resistance through the regulation of CXCL12 by sponging miR-141-3p.
Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma.
Mammary tumor-derived transplants as breast cancer models to evaluate tumor-immune interactions and therapeutic responses.
Nongenetic Cell-Intrinsic Properties Govern Malignant Clonal Fitness.
Polypharmacological reprogramming of tumor-associated macrophages towards an inflammatory phenotype.
HDAC2 facilitates pancreatic cancer metastasis.
Loss of Integrin-linked kinase sensitizes breast cancer to SRC inhibitors.
p53 partial loss-of-function mutations sensitize to chemotherapy.
Activation of PI3K/AKT pathway is a potential mechanism of treatment resistance in small cell lung cancer.
Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis.
Adipocyte-derived exosomes drive cancer metastasis.
A chemical screen based on an interruption of zebrafish gastrulation identifies the HTR2C inhibitor Pizotifen as a suppressor of EMT-mediated metastasis.
Trident cold atmospheric plasma blocks three cancer survival pathways to overcome therapy resistance.
Deciphering functional tumor states at single-cell resolution.
Live tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination.
Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia.
The role of estrogen receptor signaling in suppressing the immune response to cancer.
Transcription Factor FOSL1 Enhances Drug Resistance of Breast Cancer Through DUSP7-Mediated Dephosphorylation of PEA15.
Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer.
Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.
Targeting radiation-tolerant persister cells as a strategy for inhibiting radioresistance and recurrence in glioblastoma.
Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis.

Nat Commun. 2021 Dec 13. 12(1): 7216

Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response.

Ruhul Amin, Anjali Shukla, Jacqueline Jufen Zhu, Sohyoung Kim, Ping Wang, Simon Zhongyuan Tian, Andy D Tran, Debasish Paul, Steven D Cappell, Sandra Burkett, Huaitian Liu, Maxwell P Lee, Michael J Kruhlak, Jennifer E Dwyer, R Mark Simpson, Gordon L Hager, Yijun Ruan, Kent W Hunter.

Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identify nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 and differentially reposition within the nucleus. Transcriptional repression in Nup210 knockout cells results in defective mechanotransduction and focal adhesion necessary for their metastatic capacity. Our study provides an important role of nuclear pore protein in cellular mechanosensation and metastasis.

DOI: https://doi.org/10.1038/s41467-021-27451-w
Cancer Discov. 2021 Dec 15. pii: candisc.1265.2020. [Epub ahead of print]

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer.

Chewei Anderson Chang, Jayu Jen, Shaowen Jiang, Azin Sayad, Arvind Singh Mer, Kevin R Brown, Allison M L Nixon, Avantika Dhabaria, Kwan Ho Tang, David Venet, Christos Sotiriou, Jiehui Deng, Kwok-Kin Wong, Sylvia Adams, Peter Meyn, Adriana Heguy, Jane A Skok, Aristotelis Tsirigos, Beatrix Ueberheide, Jason Moffat, Abhyudai Singh, Benjamin Haibe-Kains, Alireza Khodadadi-Jamayran, Benjamin G Neel.

Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single cell RNA-sequencing reveal that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting show that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.

DOI: https://doi.org/10.1158/2159-8290.CD-20-1265
Cancer Res. 2021 Dec 16. pii: canres.CAN-21-3908-A.2021. [Epub ahead of print]

An in vivo CRISPR screen identifies stepwise genetic dependencies of metastatic progression.

Manuel C Scheidmann, Francesc Castro-Giner, Karin Strittmatter, Ilona Krol, Aino Paasinen-Sohns, Ramona Scherrer, Cinzia Donato, Sofia Gkountela, Barbara M Szczerba, Zoi Diamantopoulou, Simone Muenst, Tatjana Vlajnic, Leo Kunz, Marcus Vetter, Christoph Rochlitz, Verdon Taylor, Claudio Giachino, Timm Schroeder, Randall J Platt, Nicola Aceto.

Blood-borne metastasis of breast cancer involves a series of tightly regulated sequential steps, including the growth of a primary tumor lesion, intravasation of circulating tumor cells (CTC) and adaptation in various distant metastatic sites. The genes orchestrating each of these steps are poorly understood in physiologically relevant contexts, owing to the rarity of experimental models that faithfully recapitulate the biology, growth kinetics and tropism of human breast cancer. Here, we conducted an in vivo loss-of-function CRISPR screen in newly derived CTC xenografts, unique in their ability to spontaneously mirror the human disease, and identified specific genetic dependencies for each step of the metastatic process. Validation experiments revealed sensitivities to inhibitors that are already available, such as PLK1 inhibitors, to prevent CTC intravasation. Together, these findings present a new tool to reclassify driver genes involved in the spread of human cancer, providing insights into the biology of metastasis and paving the way to test targeted treatment approaches.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3908
Cancer Res. 2021 Dec 15. pii: canres.CAN-21-2745-E.2021. [Epub ahead of print]

Integrated Metabolic Profiling and Transcriptional Analysis Reveals Therapeutic Modalities for Targeting Rapidly Proliferating Breast Cancers.

Chengheng Liao, Cherise Ryan Glodowski, Cheng Fan, Juan Liu, Kevin R Mott, Akash Kaushik, Hieu Vu, Jason W Locasale, Samuel K McBrayer, Ralph J DeBerardinis, Charles M Perou, Qing Zhang.

Metabolic dysregulation is a prominent feature in breast cancer, but it remains poorly characterized in patient tumors. In this study, untargeted metabolomics analysis of triple-negative breast cancer (TNBC) and estrogen receptor (ER)-positive breast cancer patient samples, as well as TNBC patient-derived xenografts (PDX), revealed two major metabolic groups independent of breast cancer histological subtypes: a "Nucleotide/Carbohydrate-Enriched" group and a "Lipid/Fatty Acid-Enriched" group. Cell lines grown in vivo more faithfully recapitulated the metabolic profiles of patient tumors compared to those grown in vitro. Integrated metabolic and gene expression analyses identified genes that strongly correlate with metabolic dysregulation and predict patient prognosis. As a proof-of-principle, targeting Nucleotide/Carbohydrate-Enriched TNBC cell lines or PDX xenografts with a pyrimidine biosynthesis inhibitor or a glutaminase inhibitor led to therapeutic efficacy. In multiple in vivo models of TNBC, treatment with the pyrimidine biosynthesis inhibitor conferred better therapeutic outcomes than chemotherapeutic agents. This study provides a metabolic stratification of breast tumor samples that can guide the selection of effective therapeutic strategies targeting breast cancer subsets. In addition, we have developed a public, interactive data visualization portal (http://brcametab.org) based on the data generated from this study to facilitate future research.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-2745
Cancer Res. 2021 Dec 15. 81(24): 6074-6077

How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer.

Johann S Bergholz, Jean J Zhao.

Therapeutic resistance to targeted therapies by tumor cells is a common and serious problem in the clinic. Increased understanding of the molecular mechanisms that underly resistance is necessary for the rational design and improvement of effective pharmacologic treatment strategies. The landmark study by O'Reilly and colleagues published in Cancer Research in 2006 provided valuable insights into nongenomic adaptive rewiring and compensatory mechanisms responsible for mediating resistance to targeted inhibition of the PI3K-AKT-mTOR pathway, and how tumor cells regulate signaling pathways via negative feedback loops. These findings have proven fundamental for guiding current efforts to develop effective combination treatments and provided a blueprint for research studies aimed at understanding the intricacies of cellular signaling.See related article by O'Reilly and colleagues, Cancer Res 2006;66:1500-8.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3605
Nat Commun. 2021 Dec 15. 12(1): 7311

Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis.

Divya Ramchandani, Mirela Berisa, Diamile A Tavarez, Zhuoning Li, Matthew Miele, Yang Bai, Sharrell B Lee, Yi Ban, Noah Dephoure, Ronald C Hendrickson, Suzanne M Cloonan, Dingcheng Gao, Justin R Cross, Linda T Vahdat, Vivek Mittal.

Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression. The orally bioavailable copper chelating agent tetrathiomolybdate (TM) has been associated with a significant survival benefit in high-risk triple negative breast cancer (TNBC) patients. Despite these promising data, the mechanisms by which copper depletion impacts metastasis are poorly understood and this remains a major barrier to advancing TM to a randomized phase II trial. Here, using two independent TNBC models, we report a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit elevated intracellular copper levels and a marked sensitivity to TM. Global proteomic and metabolomic profiling identifies TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We also identify AMPK/mTORC1 energy sensor as an important downstream pathway and show that AMPK inhibition rescues TM-mediated loss of invasion. Furthermore, loss of the mitochondria-specific copper chaperone, COX17, restricts copper deficiency to mitochondria and phenocopies TM-mediated alterations. These findings identify a copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials.

DOI: https://doi.org/10.1038/s41467-021-27559-z
Mol Cancer. 2021 Dec 15. 20(1): 166

The circular RNA circDLG1 promotes gastric cancer progression and anti-PD-1 resistance through the regulation of CXCL12 by sponging miR-141-3p.

Dong-Liang Chen, Hui Sheng, Dong-Sheng Zhang, Ying Jin, Bai-Tian Zhao, Nuo Chen, Kang Song, Rui-Hua Xu.

   BACKGROUND: Dysregulation of circular RNAs (circRNAs) plays an important role in the development of gastric cancer; thus, revealing the biological and molecular mechanisms of abnormally expressed circRNAs is critical for identifying novel therapeutic targets in gastric cancer.
METHODS: A circRNA microarray was performed to identify differentially expressed circRNAs between primary and distant metastatic tissues and between gastric cancer tissues sensitive or resistant to anti-programmed cell death 1 (PD-1) therapy. The expression of circRNA discs large homolog 1 (DLG1) was determined in a larger cohort of primary and distant metastatic gastric cancer tissues. The role of circDLG1 in gastric cancer progression was evaluated both in vivo and in vitro, and the effect of circDLG1 on the antitumor activity of anti-PD-1 was evaluated in vivo. The interaction between circDLG1 and miR-141-3p was assessed by RNA immunoprecipitation and luciferase assays.
RESULTS: circDLG1 was significantly upregulated in distant metastatic lesions and gastric cancer tissues resistant to anti-PD-1 therapy and was associated with an aggressive tumor phenotype and adverse prognosis in gastric cancer patients treated with anti-PD-1 therapy. Ectopic circDLG1 expression promoted the proliferation, migration, invasion, and immune evasion of gastric cancer cells. Mechanistically, circDLG1 interacted with miR-141-3p and acted as a miRNA sponge to increase the expression of CXCL12, which promoted gastric cancer progression and resistance to anti-PD-1-based therapy.
CONCLUSIONS: Overall, our findings demonstrate how circDLG1 promotes gastric cancer cell proliferation, migration, invasion and immune evasion and provide a new perspective on the role of circRNAs during gastric cancer progression.

Keywords:  Gastric cancer; Immune evasion; Invasion; Proliferation; circDLG1

DOI:  https://doi.org/10.1186/s12943-021-01475-8
Cancer Res. 2021 Dec 13. pii: canres.0810.2021. [Epub ahead of print]

Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma.

Arko Sen, Briana C Prager, Cuiqing Zhong, Donglim Park, Zhe Zhu, Ryan C Gimple, Qiulian Wu, Jean A Bernatchez, Sungjun Beck, Alex E Clark, Jair L Siqueira-Neto, Jeremy N Rich, Graham McVicker.

Glioblastoma is the most prevalent primary malignant brain tumor in adults and is characterized by poor prognosis and universal tumor recurrence. Effective glioblastoma treatments are lacking, in part due to somatic mutations and epigenetic reprogramming that alter gene expression and confer drug resistance. To investigate recurrently dysregulated genes in glioblastoma we interrogated allele-specific expression (ASE), the difference in expression between two alleles of a gene, in glioblastoma stem cells (GSC) derived from 43 patients. A total of 118 genes were found with recurrent ASE preferentially in GSCs compared to normal tissues. These genes were enriched for apoptotic regulators, including schlafen family member 11 (SLFN11). Loss of SLFN11 gene expression was associated with aberrant promoter methylation and conferred resistance to chemotherapy and PARP inhibition. Conversely, low SLFN11 expression rendered GSCs susceptible to the oncolytic flavivirus Zika. This discovery effort based upon ASE revealed novel points of vulnerability in GSCs, suggesting a potential alternative treatment strategy for chemotherapy resistant glioblastoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0810
Cancer Res. 2021 Dec 13. pii: canres.0253.2021. [Epub ahead of print]

Mammary tumor-derived transplants as breast cancer models to evaluate tumor-immune interactions and therapeutic responses.

Jade Moore, Lin Ma, Ann Lazar, Mary Helen Barcellos-Hoff.

In breast cancer, the type and distribution of infiltrating immune cells are associated with clinical outcome. Moreover, infiltrated cancers with abundant tumor infiltrating lymphocytes (TIL) are more likely to respond to immunotherapy, while those in which CD8+ T cells are completely absent (deserts) or excluded are less likely to respond. Detailed understanding of this biology is limited by a lack of preclinical breast cancer models that recapitulate TIL distributions and their associated biology. Here we established mammary tumor-derived transplants (mTDT) from 12 Trp53 null mammary tumors in syngeneic BALB/cJ mice and examined the stability of their growth rate, TIL distribution, and transcriptomic profiles. All mTDT were estrogen receptor negative. Half of the parental tumors were classified as infiltrated, and the rest were divided between excluded and desert phenotypes. After two orthotopic passages, most (70%) mTDT from infiltrated parents recapitulated this pattern, whereas the desert or excluded parental patterns were maintained in about half of daughter mTDT. Approximately 30% of mTDT gave rise to lung or liver metastases, but metastasis was not associated with a TIL phenotype. Unsupervised transcriptomic analysis clustered mTDT according to their TIL spatial patterns. Infiltrated mTDT transplanted subcutaneously and orthotopically were resistant to anti-PD-L1. Profiling implicated prolonged antigen stimulation and loss of effector function of lymphocytes rather than T cell exhaustion in the lack of response of infiltrated mTDT to checkpoint blockade. In summary, the molecular diversity and immune complexity of mTDT will facilitate the dissection of mechanisms of breast cancer response to immunotherapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0253
Cancer Discov. 2021 Dec 17.

Nongenetic Cell-Intrinsic Properties Govern Malignant Clonal Fitness.

Cell-intrinsic, heritable clonal fitness is characterized by increased transcriptional heterogeneity.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-179
Cancer Res. 2021 Dec 13. pii: canres.1428.2021. [Epub ahead of print]

Polypharmacological reprogramming of tumor-associated macrophages towards an inflammatory phenotype.

Nao Nishida-Aoki, Taranjit S Gujral.

Tumor-associated macrophages (TAM) are an important component of the tumor microenvironment (TME) that can promote tumor progression, metastasis, and resistance to therapies. Although TAMs represent a promising target for therapeutic intervention, the complexity of the TME has made the study of TAMs challenging. Here, we established a physiologically relevant in vitro TAM polarization system that recapitulates TAM pro-tumoral activities. This system was used to characterize dynamic changes in gene expression and protein phosphorylation during TAM polarization and to screen phenotypic kinase inhibitors that impact TAM programming. BMS-794833, a multi-targeted compound, was identified as a potent inhibitor of TAM polarization. BMS-794833 decreased pro-tumoral properties of TAMs in vitro and suppressed tumor growth in mouse triple-negative breast cancer models. The effect of BMS-794833 was independent of its primary targets (MET and VEGFR2) but was dependent on its effect on multiple signaling pathways, including focal adhesion kinases, SRC family kinases, STAT3, and p38 MAP kinases. Collectively, these findings underline the efficacy of polypharmacological strategies in reprogramming complex signaling cascades activated during TAM polarization.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-1428
Cancer Res. 2021 Dec 13. pii: canres.3209.2020. [Epub ahead of print]

HDAC2 facilitates pancreatic cancer metastasis.

Lukas Krauß, Bettina C Urban, Sieglinde Hastreiter, Carolin Schneider, Patrick Wenzel, Zonera Hassan, Matthias Wirth, Katharina Lankes, Andrea Terrasi, Christine Klement, Filippo M Cernilogar, Rupert Ollinger, Niklas de Andrade Krätzig, Thomas Engleitner, Roland M Schmid, Katja Steiger, Roland Rad, Oliver H Krämer, Maximilian Reichert, Gunnar Schotta, Dieter Saur, Günter Schneider.

The mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly associated with metastasis, a multi-step process that is incompletely understood in this disease. Although genetic drivers of PDAC metastasis have not been defined, transcriptional and epigenetic rewiring can contribute to the metastatic process. The epigenetic eraser histone deacetylase 2 (HDAC2) has been connected to less differentiated PDAC, but the function of HDAC2 in PDAC has not been comprehensively evaluated. Using genetically defined models, we show that HDAC2 is a cellular fitness factor that controls cell cycle in vitro and metastasis in vivo, particularly in undifferentiated, mesenchymal PDAC cells. Unbiased expression profiling detected a core set of HDAC2-regulated genes. HDAC2 controlled expression of several pro-survival receptor tyrosine kinases connected to mesenchymal PDAC, including PDGFRα, PDGFRβ, and EGFR. The HDAC2-maintained program disabled the tumor-suppressive arm of the TGFβ-pathway, explaining impaired metastasis formation of HDAC2-deficient PDAC. This data identifies HDAC2 as a tractable player in the PDAC metastatic cascade. The complexity of the function of epigenetic regulators like HDAC2 implicates that an increased understanding of these proteins is needed for implementation of effective epigenetic therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-3209
Cancer Res. 2021 Dec 17. pii: canres.0373.2021. [Epub ahead of print]

Loss of Integrin-linked kinase sensitizes breast cancer to SRC inhibitors.

Henry Beetham, Billie G C Griffith, Olga Murina, Alexander Ep Loftus, David A Parry, Carolin Temps, Jayne Culley, Morwenna Muir, Asier Unciti-Broceta, Andrew H Sims, Adam Byron, Valerie G Brunton.

SRC is a non-receptor tyrosine kinase with key roles in breast cancer development and progression. Despite this, SRC tyrosine kinase inhibitors have so far failed to live up to their promise in clinical trials, with poor overall response rates. We aimed to identify possible synergistic gene-drug interactions to discover new rational combination therapies for SRC inhibitors. An unbiased genome-wide CRISPR-Cas9 knockout screen in a model of triple-negative breast cancer revealed that loss of Integrin-linked kinase (ILK) and its binding partners α-Parvin and PINCH-1 sensitizes cells to bosutinib, a clinically approved SRC/ABL kinase inhibitor. Sensitivity to bosutinib did not correlate with ABL dependency; instead, bosutinib likely induces these effects by acting as a SRC tyrosine kinase inhibitor. Furthermore, in vitro and in vivo models showed that loss of ILK enhanced sensitivity to eCF506, a novel and highly selective inhibitor of SRC with a unique mode of action. Whole-genome RNA sequencing following bosutinib treatment in ILK knockout cells identified broad changes in the expression of genes regulating cell adhesion and cell-extracellular matrix. Increased sensitivity to SRC inhibition in ILK knockout cells was associated with defective adhesion, resulting in reduced cell number as well as increased G1 arrest and apoptosis. These findings support the potential of ILK loss as an exploitable therapeutic vulnerability in breast cancer, enhancing the effectiveness of clinical SRC inhibitors.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0373
Oncogene. 2021 Dec 14.

p53 partial loss-of-function mutations sensitize to chemotherapy.

Boris Klimovich, Nastasja Merle, Michelle Neumann, Sabrina Elmshäuser, Andrea Nist, Marco Mernberger, Daniel Kazdal, Albrecht Stenzinger, Oleg Timofeev, Thorsten Stiewe.

The tumor suppressive transcription factor p53 is frequently inactivated in cancer cells by missense mutations that cluster in the DNA binding domain. 30% hit mutational hotspot residues, resulting in a complete loss of transcriptional activity and mutant p53-driven chemotherapy resistance. Of the remaining 70% of non-hotspot mutants, many are partial loss-of-function (partial-LOF) mutants with residual transcriptional activity. The therapeutic consequences of a partial-LOF have remained largely elusive. Using a p53 mutation engineered to reduce DNA binding, we demonstrate that partial-LOF is sufficient to enhance oncogene-driven tumorigenesis in mouse models of lung and pancreatic ductal adenocarcinoma and acute myeloid leukemia. Interestingly, mouse and human tumors with partial-LOF mutations showed mutant p53 protein accumulation similar as known for hotspot mutants. Different from the chemotherapy resistance caused by p53-loss, the partial-LOF mutant sensitized to an apoptotic chemotherapy response and led to a survival benefit. Mechanistically, the pro-apoptotic transcriptional activity of mouse and human partial-LOF mutants was rescued at high mutant protein levels, suggesting that accumulation of partial-LOF mutants enables the observed apoptotic chemotherapy response. p53 non-hotspot mutants with partial-LOF, therefore, represent tumorigenic p53 mutations that need to be distinguished from other mutations because of their beneficial impact on survival in a therapy context.

DOI: https://doi.org/10.1038/s41388-021-02141-5
Clin Cancer Res. 2021 Dec 17. pii: clincanres.1943.2021. [Epub ahead of print]

Activation of PI3K/AKT pathway is a potential mechanism of treatment resistance in small cell lung cancer.

Ying Jin, Yamei Chen, Huarong Tang, Shawna M Hubert, Qian Li, Xiao Hu, Dan Su, Haimiao Xu, Yun Fan, Xinmin Yu, Qixun Chen, Jinshi Liu, Wei Hong, Yujin Xu, Huan Deng, Dapeng Zhu, Pansong Li, Yuhua Gong, Xuefeng Xia, Carl M Gay, Jianjun Zhang, Ming Chen.

PURPOSE: Here we have investigated treatment resistance mechanisms in small-cell lung cancer (SCLC) by focusing on comparing the genotype and phenotype in tumor samples of treatment-resistant and treatment-sensitive SCLC.
METHODS: We conducted whole-exome sequencing (WES) on paired tumor samples at diagnosis and relapse from 11 limited-stage (LS)-SCLC patients and targeted sequencing of 1,021 cancer-related genes on cell free DNA (cfDNA) at baseline and paired relapsed samples from 9 additional LS-SCLC patients. Furthermore, we performed label-free mass spectrometry- (MS-) based proteomics on tumor samples from 28 chemo-resistant and 23 chemo-sensitive patients with extensive-stage (ES)-SCLC. The main findings were validated in vitro in chemo-sensitive versus chemo-resistant SCLC cell lines and analyses of transcriptomic data of SCLC cell lines from a public database.
RESULTS: Genomic analyses demonstrated that at relapse of LS-SCLC, genes in the PI3K/AKT signaling pathway were enriched for acquired somatic mutations or high frequency acquired CNVs. Pathway analysis on differentially upregulated proteins from ES-SCLC cohort revealed enrichment in the HIF-1 signaling pathway. Importantly, 7 of 62 PI3K/AKT pathway genes containing acquired somatic copy number amplifications were enriched in HIF-1 pathway. Analyses of transcriptomic data of SCLC cell lines from public databases confirmed upregulation of PI3K/AKT and HIF-1 pathways in chemo-resistant SCLC cell lines. Furthermore, chemotherapy-resistant cell lines could be sensitive to PI3K inhibitors in vitro Conclusions: PI3K/AKT pathway activation may be one potential mechanism underlying therapeutic resistance of SCLC. This finding warrants further investigation and provides a possible approach to reverse resistance to chemo/radiotherapy.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-1943
J Exp Med. 2022 Jan 03. pii: e20201039. [Epub ahead of print]219(1):

Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis.

Julia Bolik, Freia Krause, Marija Stevanovic, Monja Gandraß, Ilka Thomsen, Sarah-Sophie Schacht, Eva Rieser, Miryam Müller, Neele Schumacher, Jürgen Fritsch, Rielana Wichert, Eithan Galun, Juri Bergmann, Christian Röder, Clemens Schafmayer, Jan-Hendrik Egberts, Christoph Becker-Pauly, Paul Saftig, Ralph Lucius, Wulf Schneider-Brachert, Roja Barikbin, Dieter Adam, Matthias Voss, Wolfgang Hitzl, Achim Krüger, Boris Strilic, Irit Sagi, Henning Walczak, Stefan Rose-John, Dirk Schmidt-Arras.

Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell-induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapies.

DOI: https://doi.org/10.1084/jem.20201039
Nat Rev Endocrinol. 2021 Dec 16.

Adipocyte-derived exosomes drive cancer metastasis.

Olivia Tysoe.

DOI: https://doi.org/10.1038/s41574-021-00622-x
Elife. 2021 Dec 17. pii: e70151. [Epub ahead of print]10

A chemical screen based on an interruption of zebrafish gastrulation identifies the HTR2C inhibitor Pizotifen as a suppressor of EMT-mediated metastasis.

Joji Nakayama, Lora Tan, Yan Li, Boon Cher Goh, Shu Wang, Hideki Makinoshima, Zhiyuan Gong.

  Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in five hours. The screen tested 1280 FDA-approved drugs and identified Pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacologic and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with Pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt-signaling. In contrast, HTR2C induced epithelial to mesenchymal transition (EMT) through activation of Wnt-signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs.

Keywords:  developmental biology; zebrafish

DOI:  https://doi.org/10.7554/eLife.70151
Proc Natl Acad Sci U S A. 2021 Dec 21. pii: e2107220118. [Epub ahead of print]118(51):

Trident cold atmospheric plasma blocks three cancer survival pathways to overcome therapy resistance.

Bo Guo, Anthony D Pomicter, Francis Li, Sudhir Bhatt, Chen Chen, Wen Li, Miao Qi, Chen Huang, Michael W Deininger, Michael G Kong, Hai-Lan Chen.

  Therapy resistance is responsible for most cancer-related death and is mediated by the unique ability of cancer cells to leverage metabolic conditions, signaling molecules, redox status, and other pathways for their survival. Interestingly, many cancer survival pathways are susceptible to disturbances in cellular reactive oxygen species (ROS) and may therefore be disrupted by exogenous ROS. Here, we explore whether trident cold atmospheric plasma (Tri-CAP), a gas discharge with exceptionally low-level ROS, could inhibit multiple cancer survival pathways together in a murine cell line model of therapy-resistant chronic myeloid leukemia (CML). We show that Tri-CAP simultaneously disrupts three cancer survival pathways of redox deregulation, glycolysis, and proliferative AKT/mTOR/HIF-1α signaling in this cancer model. Significantly, Tri-CAP blockade induces a very high rate of apoptotic death in CML cell lines and in primary CD34+ hematopoietic stem and progenitor cells from CML patients, both harboring the therapy-resistant T315I mutation. In contrast, nonmalignant controls are minimally affected by Tri-CAP, suggesting it selectively targets resistant cancer cells. We further demonstrate that Tri-CAP elicits similar lethality in human melanoma, breast cancer, and CML cells with disparate, resistant mechanisms and that it both reduces tumor formation in two mouse models and improves survival of tumor-bearing mice. For use in patients, administration of Tri-CAP may be extracorporeal for hematopoietic stem cell transplantation therapy, transdermal, or through its activated solution for infusion therapy. Collectively, our results suggest that Tri-CAP represents a potent strategy for disrupting cancer survival pathways and overcoming therapy resistance in a variety of malignancies.

Keywords:  cancer survival pathways; chronic myeloid leukemia; cold atmospheric plasma; therapy-resistant cancers

DOI:  https://doi.org/10.1073/pnas.2107220118
EMBO J. 2021 Dec 17. e109221

Deciphering functional tumor states at single-cell resolution.

Rolando Vegliante, Ievgenia Pastushenko, Cédric Blanpain.

  Within a tumor, cancer cells exist in different states that are associated with distinct tumor functions, including proliferation, differentiation, invasion, metastasis, and resistance to anti-cancer therapy. The identification of the gene regulatory networks underpinning each state is essential for better understanding functional tumor heterogeneity and revealing tumor vulnerabilities. Here, we review the different studies identifying tumor states by single-cell sequencing approaches and the mechanisms that promote and sustain these functional states and regulate their transitions. We also describe how different tumor states are spatially distributed and interact with the specific stromal cells that compose the tumor microenvironment. Finally, we discuss how the understanding of tumor plasticity and transition states can be used to develop new strategies to improve cancer therapy.

Keywords:  EMT; cancer therapy; metastasis; single-cell; tumor heterogeneity

DOI:  https://doi.org/10.15252/embj.2021109221
Nat Commun. 2021 Dec 15. 12(1): 7300

Live tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination.

Ved P Sharma, Binwu Tang, Yarong Wang, Camille L Duran, George S Karagiannis, Emily A Xue, David Entenberg, Lucia Borriello, Anouchka Coste, Robert J Eddy, Gina Kim, Xianjun Ye, Joan G Jones, Eli Grunblatt, Nathan Agi, Sweta Roy, Gargi Bandyopadhyaya, Esther Adler, Chinmay R Surve, Dominic Esposito, Sumanta Goswami, Jeffrey E Segall, Wenjun Guo, John S Condeelis, Lalage M Wakefield, Maja H Oktay.

Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. Here, we employ high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. Substantial enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent >60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch-Jagged signaling. In breast cancers from patients, the density of TMEM doorways correlates with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites.

DOI: https://doi.org/10.1038/s41467-021-27308-2
Nat Commun. 2021 Dec 13. 12(1): 7244

Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia.

Brooks A Benard, Logan B Leak, Armon Azizi, Daniel Thomas, Andrew J Gentles, Ravindra Majeti.

The impact of clonal heterogeneity on disease behavior or drug response in acute myeloid leukemia remains poorly understood. Using a cohort of 2,829 patients, we identify features of clonality associated with clinical features and drug sensitivities. High variant allele frequency for 7 mutations (including NRAS and TET2) associate with dismal prognosis; elevated GATA2 variant allele frequency correlates with better outcomes. Clinical features such as white blood cell count and blast percentage correlate with the subclonal abundance of mutations such as TP53 and IDH1. Furthermore, patients with cohesin mutations occurring before NPM1, or transcription factor mutations occurring before splicing factor mutations, show shorter survival. Surprisingly, a branched pattern of clonal evolution is associated with superior clinical outcomes. Finally, several mutations (including NRAS and IDH1) predict drug sensitivity based on their subclonal abundance. Together, these results demonstrate the importance of assessing clonal heterogeneity with implications for prognosis and actionable biomarkers for therapy.

DOI: https://doi.org/10.1038/s41467-021-27472-5
J Clin Invest. 2021 Dec 15. pii: e155476. [Epub ahead of print]131(24):

The role of estrogen receptor signaling in suppressing the immune response to cancer.

James M Rae, Marc E Lippman.

Immune checkpoint blockade (ICB) therapies are standard of care for the treatment of many solid tumors. While some patients with cancer experience exceptional and long-term responses, intrinsic and acquired mechanisms of resistance limit the clinical efficacy of ICBs. In addition, ICBs can elicit life-threatening side effects. Alternative options that can increase ICB responses without added toxicities are needed. In this issue of the JCI, Chakraborty et al. explored the role of estrogen receptor α (ERα) in modulating ICB activity. Using transcriptomics and preclinical melanoma models, the authors show that ERα signaling in tumor-associated macrophages contributed to an immune-suppressive state within the tumor microenvironment (TME) by promoting CD8+ T cell dysfunction and exhaustion. Further, in murine melanoma models, the addition of fulvestrant, a selective estrogen receptor downregulator (SERD) approved for the treatment of breast cancer, enhanced the antitumor effects of ICB. These results provide a rationale for human trials to test the combination of antiestrogens with ICBs.

DOI: https://doi.org/10.1172/JCI155476
Mol Cancer Res. 2021 Dec 14. pii: molcanres.0658.2021. [Epub ahead of print]

Transcription Factor FOSL1 Enhances Drug Resistance of Breast Cancer Through DUSP7-Mediated Dephosphorylation of PEA15.

Lin Li, Nan Wang, Youyi Xiong, Guangcheng Guo, Mingzhi Zhu, Yuanting Gu.

Breast cancer (BC) represents one of the commonest and deadliest malignancies in women. However, drug resistance has always been a major obstacle to cancer treatment. Transcription factors have been reported to have close association with drug resistance of tumors. Recently, by analyzing the data from Gene Expression Omnibus (GEO) database (id: GSE76540), we found that transcription factor FOSL1 was significantly up-regulated in the transcriptome of doxorubicin-resistant BC cells compared with that in sensitive parental cells. Therefore, we aim to explore the regulatory mechanism of FOSL1 in affecting the drug resistance of BC cells. FOSL1 expression in doxorubicin-resistant BC cells was firstly examined through RT-qPCR, and then its influence on the drug resistance of BC cells was explored through a series of in vitro and in vivo mechanism assays. Results showed that FOSL1 promoted the drug resistance of BC cells to doxorubicin both in intro and in vivo. It positively regulated the transcription of DUSP7 in BC doxorubicin-resistant cells and DUSP7 also enhanced the drug resistance of BC cells. Furthermore, FOSL1 promoted the dephosphorylation of PEA15 through DUSP7. In conclusion, it was verified that FOSL1 promoted the drug resistance in breast cancer through DUSP7-mediated dephosphorylation of PEA15. Implications: These initial findings suggest that the FOSL1/DUSP7/PEA15 pathway may provide a theoretical guidance for BC treatment.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0658
J Exp Med. 2022 Feb 07. pii: e20210564. [Epub ahead of print]219(2):

Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer.

Michela Masetti, Roberta Carriero, Federica Portale, Giulia Marelli, Nicolò Morina, Marta Pandini, Marta Iovino, Bianca Partini, Marco Erreni, Andrea Ponzetta, Elena Magrini, Piergiuseppe Colombo, Grazia Elefante, Federico Simone Colombo, Joke M M den Haan, Clelia Peano, Javier Cibella, Alberto Termanini, Paolo Kunderfranco, Jolanda Brummelman, Matthew Wai Heng Chung, Massimo Lazzeri, Rodolfo Hurle, Paolo Casale, Enrico Lugli, Ronald A DePinho, Subhankar Mukhopadhyay, Siamon Gordon, Diletta Di Mitri.

Tumor-associated macrophages (TAMs) are correlated with the progression of prostatic adenocarcinoma (PCa). The mechanistic basis of this correlation and therapeutic strategies to target TAMs in PCa remain poorly defined. Here, single-cell RNA sequencing was used to profile the transcriptional landscape of TAMs in human PCa, leading to identification of a subset of macrophages characterized by dysregulation in transcriptional pathways associated with lipid metabolism. This subset of TAMs correlates positively with PCa progression and shorter disease-free survival and is characterized by an accumulation of lipids that is dependent on Marco. Mechanistically, cancer cell-derived IL-1β enhances Marco expression on macrophages, and reciprocally, cancer cell migration is promoted by CCL6 released by lipid-loaded TAMs. Moreover, administration of a high-fat diet to tumor-bearing mice raises the abundance of lipid-loaded TAMs. Finally, targeting lipid accumulation by Marco blockade hinders tumor growth and invasiveness and improves the efficacy of chemotherapy in models of PCa, pointing to combinatorial strategies that may influence patient outcomes.

DOI: https://doi.org/10.1084/jem.20210564
Cell. 2021 Dec 08. pii: S0092-8674(21)01381-7. [Epub ahead of print]

Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.

Bob Chen, Cherie' R Scurrah, Eliot T McKinley, Alan J Simmons, Marisol A Ramirez-Solano, Xiangzhu Zhu, Nicholas O Markham, Cody N Heiser, Paige N Vega, Andrea Rolong, Hyeyon Kim, Quanhu Sheng, Julia L Drewes, Yuan Zhou, Austin N Southard-Smith, Yanwen Xu, James Ro, Angela L Jones, Frank Revetta, Lynne D Berry, Hiroaki Niitsu, Mirazul Islam, Karin Pelka, Matan Hofree, Jonathan H Chen, Siranush Sarkizova, Kimmie Ng, Marios Giannakis, Genevieve M Boland, Andrew J Aguirre, Ana C Anderson, Orit Rozenblatt-Rosen, Aviv Regev, Nir Hacohen, Kenta Kawasaki, Toshiro Sato, Jeremy A Goettel, William M Grady, Wei Zheng, M Kay Washington, Qiuyin Cai, Cynthia L Sears, James R Goldenring, Jeffrey L Franklin, Timothy Su, Won Jae Huh, Simon Vandekar, Joseph T Roland, Qi Liu, Robert J Coffey, Martha J Shrubsole, Ken S Lau.

  Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.

Keywords:  adenoma; colorectal cancer; cytotoxic; differentiation; metaplasia; multiplex; polyp; serrated; single-cell RNA-seq; stem cells

DOI:  https://doi.org/10.1016/j.cell.2021.11.031
Neuro Oncol. 2021 Dec 14. pii: noab288. [Epub ahead of print]

Targeting radiation-tolerant persister cells as a strategy for inhibiting radioresistance and recurrence in glioblastoma.

Jintao Gu, Nan Mu, Bo Jia, Qingdong Guo, Luxiang Pan, Maorong Zhu, Wangqian Zhang, Kuo Zhang, Weina Li, Meng Li, Lichun Wei, Xiaochang Xue, Yingqi Zhang, Wei Zhang.

   BACKGROUND: Compelling evidence suggests that glioblastoma (GBM) recurrence results from the expansion of a subset of tumour cells with robust intrinsic or therapy-induced radioresistance. However, the mechanisms underlying GBM radioresistance and recurrence remain elusive. To overcome obstacles in radioresistance research, we present a novel preclinical model ideally suited for radiobiological studies.
METHODS: With this model, we performed a screen and identified a radiation-tolerant persister (RTP) subpopulation. RNA sequencing was performed on RTP and parental cells to obtain mRNA and miRNA expression profiles. The regulatory mechanisms among NF-κB, YY1, miR-103a, XRCC3 and FGF2 were investigated by transcription factor activation profiling array analysis, chromatin immunoprecipitation, western blot analysis, luciferase reporter assays and the MirTrap system. Transferrin-functionalized nanoparticles (Tf-NPs) were employed to improve blood-brain barrier permeability and RTP targeting.
RESULTS: RTP cells drive radioresistance by preferentially activating DNA damage repair and promoting stemness. Mechanistic investigations showed that continual radiation activates the NF-κB signalling cascade and promotes nuclear translocation of p65, leading to enhanced expression of YY1, the transcription factor that directly suppresses miR-103a transcription. Restoring miR-103a expression under these conditions suppressed the FGF2-XRCC3 axis and decreased the radioresistance capability. Moreover, Tf-NPs improved radiosensitivity and provided a significant survival benefit.
CONCLUSIONS: We suggest that the NF-κB-YY1-miR-103a regulatory axis is indispensable for the function of RTP cells in driving radioresistance and recurrence. Thus, our results identified a novel strategy for improving survival in patients with recurrent/refractory GBM.

Keywords:  DNA damage repair; Glioblastoma; glioma stem cell; radioresistance

DOI:  https://doi.org/10.1093/neuonc/noab288
Nat Commun. 2021 Dec 17. 12(1): 7336

Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis.

Brian Y Lee, Elizabeth K J Hogg, Christopher R Below, Alexander Kononov, Adrian Blanco-Gomez, Felix Heider, Jingshu Xu, Colin Hutton, Xiaohong Zhang, Tamara Scheidt, Kenneth Beattie, Angela Lamarca, Mairéad McNamara, Juan W Valle, Claus Jørgensen.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however the effects of individual stromal subsets remain incompletely characterised. Here, we describe how heterocellular Oncostatin M (OSM) - Oncostatin M Receptor (OSMR) signalling reprograms fibroblasts, regulates tumour growth and metastasis. Macrophage-secreted OSM stimulates inflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumourigenic environment and engage tumour cell survival and migratory signalling pathways. Tumour cells implanted in Osm-deficient (Osm-/-) mice display an epithelial-dominated morphology, reduced tumour growth and do not metastasise. Moreover, the tumour microenvironment of Osm-/- animals exhibit increased abundance of α smooth muscle actin positive myofibroblasts and a shift in myeloid and T cell phenotypes, consistent with a more immunogenic environment. Taken together, these data demonstrate how OSM-OSMR signalling coordinates heterocellular interactions to drive a pro-tumourigenic environment in PDA.

DOI: https://doi.org/10.1038/s41467-021-27607-8