bims-tucedo 2022-02-27 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2022‒02‒27
23 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

A FBXO7/EYA2-SCFFBXW7 axis promotes AXL-mediated maintenance of mesenchymal and immune evasion phenotypes of cancer cells.
Tumor ENPP1(CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer.
The peroxisome proliferator-activated receptor agonist rosiglitazone specifically represses tumour metastatic potential in chromatin inaccessibility-mediated FABP4-deficient gastric cancer.
Longitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer.
Understanding Drug Sensitivity and Tackling Resistance in Cancer.
T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1.
Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.
N7-methylguanosine tRNA modification promotes tumorigenesis and chemoresistance through WNT/β-catenin pathway in nasopharyngeal carcinoma.
KDM1A promotes thyroid cancer progression and maintains stemness through the Wnt/β-catenin signaling pathway.
Stromal Oncostatin M cytokine promotes breast cancer progression by reprogramming the tumour microenvironment.
RNA-mediated immunotherapy regulating tumor immune microenvironment: next wave of cancer therapeutics.
Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival.
Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma.
A specialist-generalist framework for epithelial-mesenchymal plasticity in cancer.
A micropeptide XBP1SBM encoded by lncRNA promotes angiogenesis and metastasis of TNBC via XBP1s pathway.
Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis.
EBF1 nuclear repositioning instructs chromatin refolding to promote therapy resistance in T leukemic cells.
Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors.
Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.
Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma.
Long noncoding RNA LINC01234 promotes hepatocellular carcinoma progression through orchestrating aspartate metabolic reprogramming.
Focal adhesion kinase inhibitors, a heavy punch to cancer.
Effective drug combinations in breast, colon and pancreatic cancer cells.

Mol Cell. 2022 Feb 11. pii: S1097-2765(22)00087-9. [Epub ahead of print]

A FBXO7/EYA2-SCFFBXW7 axis promotes AXL-mediated maintenance of mesenchymal and immune evasion phenotypes of cancer cells.

Jia Z Shen, Zhixin Qiu, Qiulian Wu, Guoxin Zhang, Rebecca Harris, Dahui Sun, Juha Rantala, William D Barshop, Linjie Zhao, Deguan Lv, Kwang-Ai Won, James Wohlschlegel, Olle Sangfelt, Heike Laman, Jeremy N Rich, Charles Spruck.

  A mesenchymal tumor phenotype associates with immunotherapy resistance, although the mechanism is unclear. Here, we identified FBXO7 as a maintenance regulator of mesenchymal and immune evasion phenotypes of cancer cells. FBXO7 bound and stabilized SIX1 co-transcriptional regulator EYA2, stimulating mesenchymal gene expression and suppressing IFNα/β, chemokines CXCL9/10, and antigen presentation machinery, driven by AXL extracellular ligand GAS6. Ubiquitin ligase SCFFBXW7 antagonized this pathway by promoting EYA2 degradation. Targeting EYA2 Tyr phosphatase activity decreased mesenchymal phenotypes and enhanced cancer cell immunogenicity, resulting in attenuated tumor growth and metastasis, increased infiltration of cytotoxic T and NK cells, and enhanced anti-PD-1 therapy response in mouse tumor models. FBXO7 expression correlated with mesenchymal and immune-suppressive signatures in patients with cancer. An FBXO7-immune gene signature predicted immunotherapy responses. Collectively, the FBXO7/EYA2-SCFFBXW7 axis maintains mesenchymal and immune evasion phenotypes of cancer cells, providing rationale to evaluate FBXO7/EYA2 inhibitors in combination with immune-based therapies to enhance onco-immunotherapy responses.

Keywords:  AXL; EYA2; FBXO7; FBXW7; GAS6; anti-PD-1 therapy; immune evasion; mesenchymal phenotype

DOI:  https://doi.org/10.1016/j.molcel.2022.01.022
Cancer Discov. 2022 Jan 27. pii: candisc.0932.2021. [Epub ahead of print]

Tumor ENPP1(CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer.

Borja Ruiz-Fernandez de Cordoba, Haritz Moreno, Karmele Valencia, Naiara Perurena, Pablo Ruedas, Thomas Walle, Alberto Pezonaga-Torres, Juan Hinojosa, Elisabet Guruceaga, Antonio Pineda-Lucena, Marta Abengozar-Muela, Denis Cochonneau, Carolina Zandueta, Susana Martinez-Canarias, Alvaro Teijeira, Daniel Ajona, Sergio Ortiz-Espinosa, Xabier Morales, Carlos Ortiz de Solorzano, Marta Santisteban, Luis I Ramos-Garcia, Laura Guembe, Vratislav Strnad, Dominique Heymann, Sandra Hervas-Stubbs, Ruben Pio, Maria E Rodriguez-Ruiz, Carlos E de Andrea, Silvestre Vicent, Ignacio Melero, Fernando Lecanda, Rafael Martinez-Monge.

Locoregional failure (LRF) in breast cancer patients post-surgery and post-irradiation (IR) is linked to a dismal prognosis. In a refined new model, we identified Enpp1 (Ectonucleotide pyrophosphatase /phosphodiesterase 1/CD203a) to be closely associated with LRF. Enpp1high circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of PMN-MDSC and neutrophil extracellular traps (NET) formation. Genetic and pharmacological Enpp1 inhibition or NET blockade extend relapse-free survival. Furthermore, in combination with fractionated irradiation (FD), Enpp1 abrogation obliterates LRF. Mechanistically, Enpp1-generated adenosinergic metabolites enhance Haptoglobin (Hp) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0932
Theranostics. 2022 ;12(4): 1904-1920

The peroxisome proliferator-activated receptor agonist rosiglitazone specifically represses tumour metastatic potential in chromatin inaccessibility-mediated FABP4-deficient gastric cancer.

Qi-Yue Chen, Xiao-Bo Huang, Ya-Jun Zhao, Hua-Gen Wang, Jia-Bin Wang, Li-Chao Liu, Ling-Qian Wang, Qing Zhong, Jian-Wei Xie, Jian-Xian Lin, Jun Lu, Long-Long Cao, Mi Lin, Ru-Hong Tu, Chao-Hui Zheng, Ping Li, Chang-Ming Huang.

  Background: Efforts to prevent recurrence in gastric cancer (GC) patients are limited by current incomplete understanding of the pathological mechanisms. The present study aimed to identify novel tumour metastasis-associated genes and investigate potential value of these genes in clinical diagnosis and therapy. Methods: RNA sequencing was performed to identify differentially expressed genes related to GC metastasis. The expression and prognostic significance of fatty acid binding protein 4 (FABP4) were evaluated in two independent cohorts of GC patients. Chromatin immunoprecipitation sequencing, diverse mouse models and assays for transposase-accessible chromatin with high-throughput sequencing were used to investigate the roles and mechanisms of action of FABP4. Results: The results of the present multicentre study confirmed an association between a decrease in the expression of FABP4 and poor outcomes in GC patients. FABP4 inhibited GC metastasis but did not influence tumour growth in vitro and in vivo. Mechanistically, FABP4 binding with peroxisome proliferator-activated receptor γ (PPAR-γ) facilitated the translocation of PPAR-γ to the nucleus. FABP4 depletion suppressed PPAR-γ-mediated transcription of cell adhesion molecule 3 (CADM3), which preferentially governed GC metastasis. Notably, the PPAR-γ agonist rosiglitazone reversed the metastatic properties of FABP4-deficient GC cells in vitro and demonstrated viable therapeutic potential in multiple mouse models. For GC patients with diabetes, low FABP4 portends better prognosis than high FABP4 after receipt of rosiglitazone treatment. Additionally, chromatin inaccessibility induced by HDAC1 reduced FABP4 expression at the epigenetic level. Conclusions: Our findings suggest that chromatin inaccessibility orchestrates a reduction in FABP4 expression, which inhibits CADM3 transcription via PPAR-γ, thereby resulting in GC metastasis. The antidiabetic drug rosiglitazone restores PPAR-γ/CADM3 activation in FABP4-deficient GC and thus has promising therapeutic potential.

Keywords:  CADM3; FABP4; Gastric cancer; PPAR-γ; Rosiglitazone

DOI:  https://doi.org/10.7150/thno.66814
Sci Adv. 2022 Feb 25. 8(8): eabm1831

Longitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer.

Kaiyang Zhang, Erdogan Pekcan Erkan, Sanaz Jamalzadeh, Jun Dai, Noora Andersson, Katja Kaipio, Tarja Lamminen, Naziha Mansuri, Kaisa Huhtinen, Olli Carpén, Sakari Hietanen, Jaana Oikkonen, Johanna Hynninen, Anni Virtanen, Antti Häkkinen, Sampsa Hautaniemi, Anna Vähärautio.

Chemotherapy resistance is a critical contributor to cancer mortality and thus an urgent unmet challenge in oncology. To characterize chemotherapy resistance processes in high-grade serous ovarian cancer, we prospectively collected tissue samples before and after chemotherapy and analyzed their transcriptomic profiles at a single-cell resolution. After removing patient-specific signals by a novel analysis approach, PRIMUS, we found a consistent increase in stress-associated cell state during chemotherapy, which was validated by RNA in situ hybridization and bulk RNA sequencing. The stress-associated state exists before chemotherapy, is subclonally enriched during the treatment, and associates with poor progression-free survival. Co-occurrence with an inflammatory cancer-associated fibroblast subtype in tumors implies that chemotherapy is associated with stress response in both cancer cells and stroma, driving a paracrine feed-forward loop. In summary, we have found a resistant state that integrates stromal signaling and subclonal evolution and offers targets to overcome chemotherapy resistance.

DOI: https://doi.org/10.1126/sciadv.abm1831
Cancer Res. 2022 Feb 21. pii: canres.3695.2021. [Epub ahead of print]

Understanding Drug Sensitivity and Tackling Resistance in Cancer.

Jeffrey W Tyner, Franziska Haderk, Anbarasu Kumaraswamy, Linda B Baughn, Brian G Van Ness, Song Liu, Himangi Marathe, Joshi J Alumkal, Trever G Bivona, Keith Syson Chan, Brian J Druker, Alan D Hutson, Peter S Nelson, Charles L Sawyers, Christopher D Willey.

Decades of research into the molecular mechanisms of cancer and the development of novel therapeutics have yielded a number of remarkable successes. However, our ability to broadly assign effective, rationally targeted therapies in a personalized manner remains elusive for many patients, and drug resistance persists as a major problem. This is in part due to the well-documented heterogeneity of cancer, including the diversity of tumor cell lineages and cell states, the spectrum of somatic mutations, the complexity of microenvironments, and immune-suppressive features and immune repertoires, which collectively require numerous different therapeutic approaches. Here, we describe a framework to understand the types and biological causes of resistance, providing translational opportunities to tackle drug resistance by rational therapeutic strategies.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3695
Oncogene. 2022 Feb 26.

T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1.

Xiaoyu Ji, Xiaoping Chen, Bixiang Zhang, Meng Xie, Tongyue Zhang, Xiangyuan Luo, Danfei Liu, Yangyang Feng, Yijun Wang, Mengyu Sun, Congxin Li, Wenjie Huang, Limin Xia.

The effect of targeted therapy for metastatic hepatocellular carcinoma (HCC) is still unsatisfactory. Exploring the underlying mechanism of HCC metastasis is favorable to provide new therapeutic strategies. T-box (TBX) transcription factor family genes, which are crucial regulators in embryo and organ development, are vital for regulating tumor initiation, growth and metastasis. Here we explored the role of TBX19 in HCC metastasis, which is one of the most upregulated TBX family genes in human HCC tissues. TBX19 expression was markedly upregulated in HCC tissues and elevated TBX19 expression predicted poor prognosis. Overexpression of TBX19 enhanced HCC metastasis through upregulating epidermal growth factor receptor (EGFR) and Rac family small GTPase 1 (RAC1) expression. Downregulation of EGFR and RAC1 inhibited TBX19-mediated HCC metastasis, while upregulation of EGFR and RAC1 restored inhibition of HCC metastasis mediated by TBX19 knockdown. Furthermore, epidermal growth factor (EGF)/EGFR signaling upregulated TBX19 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor (NF)-kB axis. Besides, the combined application of EGFR inhibitor Erlotinib and RAC1 inhibitor NSC23766 markedly inhibited TBX19-mediated HCC metastasis. In HCC cohorts, TBX19 expression was positively associated with EGFR and RAC1 expression. Patients with positive coexpression of TBX19/EGFR or TBX19/RAC1 displayed the poorest prognosis. In conclusion, EGF/EGFR signaling upregulated TBX19 expression via ERK/NF-kB pathway and TBX19 fostered HCC metastasis by enhancing EGFR and RAC1 expression, which formed an EGF-TBX19-EGFR positive feedback loop. Targeting this signaling pathway may offer a potential therapeutic strategy to efficiently restrain TBX19-mediated HCC metastasis.

DOI: https://doi.org/10.1038/s41388-022-02249-2
EMBO J. 2022 Feb 25. e108272

Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.

Jorida Çoku, David M Booth, Jan Skoda, Madison C Pedrotty, Jennifer Vogel, Kangning Liu, Annette Vu, Erica L Carpenter, Jamie C Ye, Michelle A Chen, Peter Dunbar, Elizabeth Scadden, Taekyung D Yun, Eiko Nakamaru-Ogiso, Estela Area-Gomez, Yimei Li, Kelly C Goldsmith, C Patrick Reynolds, Gyorgy Hajnoczky, Michael D Hogarty.

  Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive tumors phenocopied resistance. MAMs serve as platforms to transfer Ca2+ and bioactive lipids to mitochondria. Reduced Ca2+ transfer was found in some but not all resistant cells, and inhibiting transfer did not attenuate apoptotic signaling. In contrast, reduced ceramide synthesis and transfer was common to resistant cells and its inhibition induced stress resistance. We identify ER-mitochondria-associated membranes as physiologic regulators of apoptosis via ceramide transfer and uncover a previously unrecognized mechanism for cancer multidrug resistance.

Keywords:  ceramides; inter-organelle contacts; mitochondria-associated membranes; multidrug resistance; sphingolipids

DOI:  https://doi.org/10.15252/embj.2021108272
Oncogene. 2022 Feb 26.

N7-methylguanosine tRNA modification promotes tumorigenesis and chemoresistance through WNT/β-catenin pathway in nasopharyngeal carcinoma.

Binbin Chen, Wei Jiang, Ying Huang, Jian Zhang, Peng Yu, Lirong Wu, Hao Peng.

Treatment selections are very limited for patients with advanced nasopharyngeal carcinoma (NPC) experiencing disease progression. Uncovering mechanisms underlying NPC progression is crucial for the development of novel treatments. Here we show that N7-methylguanosine (m7G) tRNA modification enzyme METTL1 and its partner WDR4 are significantly elevated in NPC and are associated with poor prognosis. Loss-of-function and gain-of-function assays demonstrated that METTL1/WDR4 promotes NPC growth and metastasis in vitro and in vivo. Mechanistically, ARNT was identified as an upstream transcription factor regulating METTL1 expression in NPC. METTL1 depletion resulted in decreased m7G tRNA modification and expression, which led to impaired codon recognition during mRNA translation, therefore reducing the translation efficiencies of mRNAs with higher m7G codons. METTL1 upregulated the WNT/β-catenin signaling pathway and promoted NPC cell epithelial-mesenchymal transition (EMT) and chemoresistance to cisplatin and docetaxel in vitro and in vivo. Overexpression of WNT3A bypassed the requirement of METTL1 for EMT and chemoresistance. This work uncovers novel insights into tRNA modification-mediated mRNA translation regulation and highlights the critical function of tRNA modification in cancer progression.

DOI: https://doi.org/10.1038/s41388-022-02250-9
Theranostics. 2022 ;12(4): 1500-1517

KDM1A promotes thyroid cancer progression and maintains stemness through the Wnt/β-catenin signaling pathway.

Wei Zhang, Xianhui Ruan, Yaoshuang Li, Jingtai Zhi, Linfei Hu, Xiukun Hou, Xianle Shi, Xin Wang, Jinpeng Wang, Weike Ma, Pengfei Gu, Xiangqian Zheng, Ming Gao.

  Background: Cancer stem cells (CSCs) are highly tumorigenic, chemotherapy-resistant, tumor growth-sustaining, and are implicated in tumor recurrence. Previous studies have shown that lysine-specific histone demethylase 1A (KDM1A) is highly expressed in several human malignancies and CSCs. However, the role of KDM1A in CSCs and the therapeutic potential of KDM1A inhibitors for the treatment of the advanced thyroid cancer are poorly understood. Methods: Firstly, KDM1A was identified as an important epigenetic modifier that maintained the stemness of thyroid cancer through a mini histone methylation modifier screen and confirmed in thyroid cancer tissues and cell lines. RNA sequence was performed to discover the downstream genes of KDM1A. The underlying mechanisms were further investigated by ChIP, IP and dual luciferase reporter assays, gain and loss of function assays. Results: Here we report that KDM1A regulates the stemness of thyroid cancer and promotes thyroid cancer progression via the Wnt/β-catenin pathway. Mechanistically, KDM1A down-regulates two antagonists of the canonical Wnt pathway, APC2 and DKK1, by demethylating H3K4me1/2 of the APC2 promoter region and the nonhistone substrate HIF-1α, resulting in the inhibition of APC2 transcription and the activation of the HIF-1α/microRNA-146a/DKK1 axis. Importantly, we also demonstrate that GSK-LSD1, a highly selective inhibitor of KDM1A, significantly inhibits thyroid cancer progression and enhances the sensitivity of thyroid cancer to chemotherapy. Conclusions: KDM1A plays an important role in thyroid cancer progression and maintains stemness, our study provides a new strategy for the therapy of advanced thyroid cancer.

Keywords:  KDMIA; Wnt/β-catenin pathway; stemness; target therapy; thyroid cancer

DOI:  https://doi.org/10.7150/thno.66142
J Clin Invest. 2022 Feb 22. pii: e148667. [Epub ahead of print]

Stromal Oncostatin M cytokine promotes breast cancer progression by reprogramming the tumour microenvironment.

Angela M Araujo, Andrea Abaurrea, Peio Azcoaga, Joanna I López-Velazco, Sara Manzano, Javier Rodriguez, Ricardo Rezola, Leire Egia-Mendikute, Fátima Valdés-Mora, Juana M Flores, Liam Jenkins, Laura Pulido, Iñaki Osorio-Querejeta, Patricia Fernández-Nogueira, Nicola Ferrari, Cristina Viera, Natalia Martin-Martin, Alexandar Tzankov, Serenella Eppenberger-Castori, Isabel Alvarez-Lopez, Ander Urruticoechea, Paloma Bragado, Nicholas Coleman, Asis Palazon, Arkaitz Carracedo, David Gallego-Ortega, Fernando Calvo, Clare M Isacke, Maria M Caffarel, Charles H Lawrie.

  The tumour microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumour progression. The contribution of stromal cells to the reprogramming of the TME is not well-understood. Here we provide solid evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and non-immune stromal cells and the epithelial cancer cell compartment. Oncostatin M Receptor (OSMR) deletion in a multistage breast cancer model halted tumour progression. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype, elicited the secretion of VEGF and pro-inflammatory chemokines CXCL1 and CXCL16, leading to increased neutrophil and macrophage recruitment. Collectively, our data support that stromal OSM:OSMR axis reprograms the immune and non-immune microenvironment and plays a key role in breast cancer progression.

Keywords:  Breast cancer; Chemokines; Cytokines; Inflammation; Oncology

DOI:  https://doi.org/10.1172/JCI148667
Mol Cancer. 2022 Feb 21. 21(1): 58

RNA-mediated immunotherapy regulating tumor immune microenvironment: next wave of cancer therapeutics.

Poonam R Pandey, Ken H Young, Dhiraj Kumar, Neeraj Jain.

  Accumulating research suggests that the tumor immune microenvironment (TIME) plays an essential role in regulation of tumor growth and metastasis. The cellular and molecular nature of the TIME influences cancer progression and metastasis by altering the ratio of immune- suppressive versus cytotoxic responses in the vicinity of the tumor. Targeting or activating the TIME components show a promising therapeutic avenue to combat cancer. The success of immunotherapy is both astounding and unsatisfactory in the clinic. Advancements in RNA-based technology have improved understanding of the complexity and diversity of the TIME and its effects on therapy. TIME-related RNA or RNA regulators could be promising targets for anticancer immunotherapy. In this review, we discuss the available RNA-based cancer immunotherapies targeting the TIME. More importantly, we summarize the potential of various RNA-based therapeutics clinically available for cancer treatment. RNA-dependent targeting of the TIME, as monotherapy or combined with other evolving therapeutics, might be beneficial for cancer patients' treatment in the near future.

Keywords:  Antibody; Cancer; Cytokine; Dendritic cells; Immunotherapy; Nanoparticle; RNA; RNA therapy; T cells; Tumor immune microenvironment

DOI:  https://doi.org/10.1186/s12943-022-01528-6
Sci Adv. 2022 Feb 25. 8(8): eabf9096

Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival.

Jessica Whitburn, Srinivasa R Rao, Emma V Morris, Sho Tabata, Akiyoshi Hirayama, Tomoyoshi Soga, James R Edwards, Zeynep Kaya, Charlotte Palmer, Freddie C Hamdy, Claire M Edwards.

The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.

DOI: https://doi.org/10.1126/sciadv.abf9096
Nat Commun. 2022 Feb 23. 13(1): 1009

Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma.

Yuen Lam Dora Ng, Evelyn Ramberger, Stephan R Bohl, Anna Dolnik, Christian Steinebach, Theresia Conrad, Sina Müller, Oliver Popp, Miriam Kull, Mohamed Haji, Michael Gütschow, Hartmut Döhner, Wolfgang Walther, Ulrich Keller, Lars Bullinger, Philipp Mertins, Jan Krönke.

The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. To identify non-genetic mechanisms of drug resistance, we here perform integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses reveal a CDK6-governed protein resistance signature that includes myeloma high-risk factors such as TRIP13 and RRM1. Overexpression of CDK6 in multiple myeloma cell lines reduces sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo. This work identifies CDK6 upregulation as a druggable target in IMiD-resistant multiple myeloma and highlights the use of proteomic studies to uncover non-genetic resistance mechanisms in cancer.

DOI: https://doi.org/10.1038/s41467-022-28515-1
Trends Cancer. 2022 Feb 17. pii: S2405-8033(22)00021-8. [Epub ahead of print]

A specialist-generalist framework for epithelial-mesenchymal plasticity in cancer.

David P Cook, Jeffrey L Wrana.

  Epithelial-mesenchymal plasticity (EMP) reflects the capacity of cells to interconvert between epithelial and mesenchymal phenotypes. In cancer, these dynamics ultimately contribute to disease progression. Despite decades of study, a consistent molecular definition of this plasticity remains elusive because of its inherent variability. The advent of quantitative single-cell biology is unveiling unexpected complexity, and new conceptual frameworks are required to understand the emergence and relevance of EMP in cancer. Here, we use principles from multitask optimization to propose that EMP reflects an adaptive response of epithelial cells in response to homeostatic disruption, giving rise to generalist phenotypes. We use this theory to predict properties of these cells and their contribution to tumor progression.

Keywords:  EMT; Pareto optimality; adaptation; epithelial-mesenchymal plasticity; evolution; plasticity

DOI:  https://doi.org/10.1016/j.trecan.2022.01.014
Oncogene. 2022 Feb 23.

A micropeptide XBP1SBM encoded by lncRNA promotes angiogenesis and metastasis of TNBC via XBP1s pathway.

Siqi Wu, Binbin Guo, Liyuan Zhang, Xun Zhu, Peipei Zhao, Jieqiong Deng, Jian Zheng, Fang Li, Yirong Wang, Shenghua Zhang, Zheng Zhang, Jiachun Lu, Yifeng Zhou.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with a poor prognosis. To date, the mechanism of TNBC's aggressive phenotype is still unclear. Based on metabolome analysis, we found that glutamine (Gln) metabolism plays a key role in the difference between TNBC and non-TNBC. We identified a 21-amino-acid survival-associated micropeptide XBP1SBM, encoded by the lncRNA MLLT4-AS1, which was upregulated in TNBC tissues and Gln-deprived TNBC cell lines. We showed that XBP1SBM expression was upregulated by Gln-deprivation-induced XBP1s transcriptional promotion, and in turn retained XBP1s in the nuclear to enhance the expression of VEGF. Using human endothelial cells, mouse xenograft models and mouse spontaneous BC models, we found that XBP1SBM improved Gln levels and promoted angiogenesis and metastasis in TNBC. Our study showed that a TNBC-specific nutrient deficiency adaption results in aggressive TNBC, and this mechanism provides a novel potential prognostic biomarker and therapeutic target in TNBC.

DOI: https://doi.org/10.1038/s41388-022-02229-6
Nat Commun. 2022 Feb 23. 13(1): 898

Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis.

Farshad Farshidfar, Kahn Rhrissorrakrai, Chaya Levovitz, Cong Peng, James Knight, Antonella Bacchiocchi, Juan Su, Mingzhu Yin, Mario Sznol, Stephan Ariyan, James Clune, Kelly Olino, Laxmi Parida, Joerg Nikolaus, Meiling Zhang, Shuang Zhao, Yan Wang, Gang Huang, Miaojian Wan, Xianan Li, Jian Cao, Qin Yan, Xiang Chen, Aaron M Newman, Ruth Halaban.

Acral melanoma, the most common melanoma subtype among non-White individuals, is associated with poor prognosis. However, its key molecular drivers remain obscure. Here, we perform integrative genomic and clinical profiling of acral melanomas from 104 patients treated in North America (n = 37) or China (n = 67). We find that recurrent, late-arising focal amplifications of cytoband 22q11.21 are a leading determinant of inferior survival, strongly associated with metastasis, and linked to downregulation of immunomodulatory genes associated with response to immune checkpoint blockade. Unexpectedly, LZTR1 - a known tumor suppressor in other cancers - is a key candidate oncogene in this cytoband. Silencing of LZTR1 in melanoma cell lines causes apoptotic cell death independent of major hotspot mutations or melanoma subtypes. Conversely, overexpression of LZTR1 in normal human melanocytes initiates processes associated with metastasis, including anchorage-independent growth, formation of spheroids, and an increase in MAPK and SRC activities. Our results provide insights into the etiology of acral melanoma and implicate LZTR1 as a key tumor promoter and therapeutic target.

DOI: https://doi.org/10.1038/s41467-022-28566-4
Mol Cell. 2022 Feb 09. pii: S1097-2765(22)00058-2. [Epub ahead of print]

EBF1 nuclear repositioning instructs chromatin refolding to promote therapy resistance in T leukemic cells.

Yeqiao Zhou, Jelena Petrovic, Jingru Zhao, Wu Zhang, Ashkan Bigdeli, Zhen Zhang, Shelley L Berger, Warren S Pear, Robert B Faryabi.

  Chromatin misfolding has been implicated in cancer pathogenesis; yet, its role in therapy resistance remains unclear. Here, we systematically integrated sequencing and imaging data to examine the spatial and linear chromatin structures in targeted therapy-sensitive and -resistant human T cell acute lymphoblastic leukemia (T-ALL). We found widespread alterations in successive layers of chromatin organization including spatial compartments, contact domain boundaries, and enhancer positioning upon the emergence of targeted therapy resistance. The reorganization of genome folding structures closely coincides with the restructuring of chromatin activity and redistribution of architectural proteins. Mechanistically, the derepression and repositioning of the B-lineage-determining transcription factor EBF1 from the heterochromatic nuclear envelope to the euchromatic interior instructs widespread genome refolding and promotes therapy resistance in leukemic T cells. Together, our findings suggest that lineage-determining transcription factors can instruct changes in genome topology as a driving force for epigenetic adaptations in targeted therapy resistance.

Keywords:  EBF1; T cell leukemia; TCF1; chromatin folding; drug resistance; epigenetic adaptation; genome topology; lineage-determining transcription factors; pioneer transcription factors; targeted therapy

DOI:  https://doi.org/10.1016/j.molcel.2022.01.015
Cell Rep. 2022 Feb 22. pii: S2211-1247(22)00142-5. [Epub ahead of print]38(8): 110418

Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors.

Nishanth Belugali Nataraj, Ashish Noronha, Joo Sang Lee, Soma Ghosh, Harsha Raj Mohan Raju, Arunachalam Sekar, Binyamin Zuckerman, Moshit Lindzen, Emilio Tarcitano, Swati Srivastava, Michael Selitrennik, Ido Livneh, Diana Drago-Garcia, Oscar Rueda, Carlos Caldas, Sima Lev, Tamar Geiger, Aaron Ciechanover, Igor Ulitsky, Rony Seger, Eytan Ruppin, Yosef Yarden.

  By establishing multi-omics pipelines, we uncover overexpression and gene copy-number alterations of nucleoporin-93 (NUP93), a nuclear pore component, in aggressive human mammary tumors. NUP93 overexpression enhances transendothelial migration and matrix invasion in vitro, along with tumor growth and metastasis in animal models. These findings are supported by analyses of two sets of naturally occurring mutations: rare oncogenic mutations and inactivating familial nephrotic syndrome mutations. Mechanistically, NUP93 binds with importins, boosts nuclear transport of importins' cargoes, such as β-catenin, and activates MYC. Likewise, NUP93 overexpression enhances the ultimate nuclear transport step shared by additional signaling pathways, including TGF-β/SMAD and EGF/ERK. The emerging addiction to nuclear transport exposes vulnerabilities of NUP93-overexpressing tumors. Congruently, myristoylated peptides corresponding to the nuclear translocation signals of SMAD and ERK can inhibit tumor growth and metastasis. Our study sheds light on an emerging hallmark of advanced tumors, which derive benefit from robust nucleocytoplasmic transport.

Keywords:  EGF/ERK; TGF-β/SMAD; WNT/β-catenin; breast cancer; cancer hallmark; importin; metastasis; nuclear pore; nuclear transport; transcription factor

DOI:  https://doi.org/10.1016/j.celrep.2022.110418
Proc Natl Acad Sci U S A. 2022 Feb 22. pii: e2107266119. [Epub ahead of print]119(8):

Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.

Zuen Ren, Huizhi Liang, Phillip M Galbo, Malindrie Dharmaratne, Ameya S Kulkarni, Atefeh Taherian Fard, Marie Louise Aoun, Nuria Martinez-Lopez, Kimita Suyama, Outhiriaradjou Benard, Wei Zheng, Yang Liu, Joseph Albanese, Deyou Zheng, Jessica C Mar, Rajat Singh, Michael B Prystowsky, Larry Norton, Rachel B Hazan.

  In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.

Keywords:  HIF1α; ROS signaling; breast cancer; glutathione peroxidase 2; metabolism

DOI:  https://doi.org/10.1073/pnas.2107266119
Clin Cancer Res. 2022 Feb 18. pii: clincanres.1060.2021. [Epub ahead of print]

Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma.

Caitlin A Creasy, Yuzhong Jeff Meng, Marie-Andrée Forget, Tatiana Karpinets, Katarzyna Tomczak, Chip Stewart, Carlos A Torres-Cabala, Shari Pilon-Thomas, Amod A Sarnaik, James J Mule, Levi Garraway, Matias Bustos, Jianhua Zhang, Sapna P Patel, Adi Diab, Isabella C Glitza, Cassian Yee, Hussein Tawbi, Michael K Wong, Jennifer McQuade, Dave S B Hoon, Michael A Davies, Patrick Hwu, Rodabe N Amaria, Cara Haymaker, Rameen Beroukhim, Chantale Bernatchez.

PURPOSE: Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40-50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.EXPERIMENTAL DESIGN: We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.
RESULTS: Whole exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR were enriched in responders who had improved PFS and OS. In contrast, the expression of ELFN1 was enriched in patients with unfavorable response, poor PFS and OS, whereas enhanced methylation of ELFN1 was observed in patients with favorable outcomes. Expression of ELFN1, NGFR and PDE1C was mainly found in cancer-associated fibroblasts and endothelial cells in tumor tissues across different cancer types in publicly available single cell RNA sequencing datasets, suggesting a role for elements of the tumor microenvironment in defining the outcome of TIL therapy.
CONCLUSIONS: Our findings suggest that transcriptional features of melanomas correlate with outcomes after TIL therapy and may provide candidates to guide patient selection.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-1060
Mol Ther. 2022 Feb 19. pii: S1525-0016(22)00104-6. [Epub ahead of print]

Long noncoding RNA LINC01234 promotes hepatocellular carcinoma progression through orchestrating aspartate metabolic reprogramming.

Muhua Chen, Chunfeng Zhang, Wei Liu, Xiaojuan Du, Xiaofeng Liu, Baocai Xing.

Amino acids metabolism, especially aspartate metabolism, is often altered in human cancers including hepatocellular carcinoma (HCC) and this metabolic remodeling is required for supporting cancer cell malignant activities. Argininosuccinate synthase 1 (ASS1), as a crucial rate-limiting enzyme in aspartate metabolism, participates in repressing tumor progression. However, the roles of long noncoding RNAs (lncRNAs) in aspartate metabolism remodeling and the underlying mechanisms remain unclear. Here, we screen LINC01234 as an aspartate metabolism-related lncRNA in HCC. Clinically, LINC01234 was highly expressed in HCC, and high LINC01234 expression level was correlated with poor prognosis of HCC patients. LINC01234 promoted cell proliferation, migration and drug-resistance by orchestrating aspartate metabolic reprogramming in HCC cells. Mechanistically, LINC01234 downregulated the expression of ASS1, leading to increased aspartate level and activation of mTOR pathway. LINC01234 bound to the promoter of ASS1 and inhibited transcriptional activation of ASS1 by transcriptional factors (TFs), including p53. Finally, inhibiting LINC01234 dramatically impaired tumor growth in nude mice and sensitized HCC cells to sorafenib. These findings demonstrate that LINC01234 promotes HCC progression by modulating aspartate metabolic reprogramming and might be a prognostic or therapeutic target for HCC.

DOI: https://doi.org/10.1016/j.ymthe.2022.02.020
Discov Oncol. 2021 Nov 22. 12(1): 52

Focal adhesion kinase inhibitors, a heavy punch to cancer.

Yueling Wu, Ning Li, Chengfeng Ye, Xingmei Jiang, Hui Luo, Baoyuan Zhang, Ying Zhang, Qingyu Zhang.

  Kinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.

Keywords:  Cancer chemotherapy; FAK inhibitors; Focal adhesion kinase

DOI:  https://doi.org/10.1007/s12672-021-00449-y
Nature. 2022 Feb 23.

Effective drug combinations in breast, colon and pancreatic cancer cells.

Patricia Jaaks, Elizabeth A Coker, Daniel J Vis, Olivia Edwards, Emma F Carpenter, Simonetta M Leto, Lisa Dwane, Francesco Sassi, Howard Lightfoot, Syd Barthorpe, Dieudonne van der Meer, Wanjuan Yang, Alexandra Beck, Tatiana Mironenko, Caitlin Hall, James Hall, Iman Mali, Laura Richardson, Charlotte Tolley, James Morris, Frances Thomas, Ermira Lleshi, Nanne Aben, Cyril H Benes, Andrea Bertotti, Livio Trusolino, Lodewyk Wessels, Mathew J Garnett.

Combinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS-TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.

DOI: https://doi.org/10.1038/s41586-022-04437-2