bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒10‒17
twenty-four papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Remodeling the ECM: Implications for Metastasis and Tumor Dormancy.
  2. Targeting LRRC15 inhibits metastatic dissemination of ovarian cancer.
  3. Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.
  4. Redox Regulation in Cancer Cells during Metastasis.
  5. Visualization of endogenous p27 and Ki67 reveals the importance of a c-Myc-driven metabolic switch in promoting survival of quiescent cancer cells.
  6. Proteomic analysis of lung cancer cells reveals a critical role of BCAT1 in cancer cell metastasis.
  7. Epigenetic Heterogeneity Controls Glioma Cell State and Stress Response.
  8. Specific activation of the CD271 intracellular domain in combination with chemotherapy or targeted therapy inhibits melanoma progression.
  9. The HNF4α-BC200-FMR1 positive feedback loop promotes growth and metastasis in invasive mucinous lung adenocarcinoma.
  10. The Polo-like kinase 1 inhibitor onvansertib represents a relevant treatment for head and neck squamous cell carcinoma resistant to cisplatin and radiotherapy.
  11. Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts.
  12. A highly annotated database of genes associated with platinum resistance in cancer.
  13. Spatially confined sub-tumor microenvironments in pancreatic cancer.
  14. Targeting KDM6A suppresses SREBP1c-dependent lipid metabolism and prostate tumorigenesis.
  15. Pathway signatures derived from on-treatment tumor specimens predict response to anti-PD1 blockade in metastatic melanoma.
  16. Homeostatic membrane tension constrains cancer cell dissemination by counteracting BAR protein assembly.
  17. Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases.
  18. Cancer Special Issue: Early detection and minimal residual disease.
  19. Accelerating precision anti-cancer therapy by time-lapse and label-free 3D tumor slice culture platform.
  20. Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis.
  21. Hypoxia drives dihydropyrimidine dehydrogenase expression in macrophages and confers chemoresistance in colorectal cancer.
  22. BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators.
  23. Generation of an orthotopic mouse model to study colorectal cancer metastasis.
  24. Necroptosis and tumor progression.
  1. Cancers (Basel). 2021 Sep 30. pii: 4916. [Epub ahead of print]13(19):
    Remodeling the ECM: Implications for Metastasis and Tumor Dormancy.
    Julie S Di Martino, Tasmiah Akhter, Jose Javier Bravo-Cordero.
      While most primary tumors can be effectively treated, therapeutics fail to efficiently eliminate metastases. Metastases arise from cancer cells that leave the primary tumor and seed distant sites. Recent studies have shown that cancer cells disseminate early during tumor progression and can remain dormant for years before they resume growth. In these metastatic organs, cancer cells reside in microenvironments where they interact with other cells, but also with the extracellular matrix (ECM). The ECM was long considered to be an inert, non-cellular component of tissues, providing their architecture. However, in recent years, a growing body of evidence has shown that the ECM is a key driver of cancer progression, and it can exert effects on tumor cells, regulating their metastatic fate. ECM remodeling and degradation is required for the early steps of the metastatic cascade: invasion, tumor intravasation, and extravasation. Similarly, ECM molecules have been shown to be important for metastatic outgrowth. However, the role of ECM molecules on tumor dormancy and their contribution to the dormancy-supportive niches is not well understood. In this perspective article, we will summarize the current knowledge of ECM and its role in tumor metastasis and dormancy. We will discuss how a better understanding of the individual components of the ECM niche and their roles mediating the dormant state of disseminated tumor cells (DTCs) will advance the development of new therapies to target dormant cells and prevent metastasis outgrowth.
    Keywords:  ECM; cancer dormancy; metastasis
    DOI:  https://doi.org/10.3390/cancers13194916
  2. Cancer Res. 2021 Oct 15. pii: canres.0622.2021. [Epub ahead of print]
    Targeting LRRC15 inhibits metastatic dissemination of ovarian cancer.
    Upasana Ray, Deok-Beom Jung, Ling Jin, Yinan Xiao, Subramanyam Dasari, Sayantani Sarkar Bhattacharya, Prabhu Thirusangu, Julie K Staub, Debarshi Roy, Bhaskar Roy, S John Weroha, Xiaonan Hou, James W Purcell, Jamie N Bakkum-Gamez, Scott H Kaufmann, Nagarajan Kannan, Anirban K Mitra, Viji Shridhar.
      Dissemination of ovarian cancer (OC) cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine-rich repeat-containing membrane protein, highly overexpressed in OC bowel metastases compared to matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of OC demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum. Mechanistically, LRRC15 interacted with β1-integrin to stimulate activation of focal adhesion kinase (FAK) signaling. As a therapeutic proof of concept, targeting LRRC15 with the specific antibody-drug conjugate ABBV-085 in both early and late metastatic OC cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived OC xenograft models. Furthermore, treatment of 3D-spheroid cultures of LRRC15-positive patient-derived ascites with ABBV-085 reduced cell viability. Overall, these data uncover a role for LRRC15 in promoting OC metastasis and suggest a novel and promising therapy to target OC metastases.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0622
  3. Cancer Cell. 2021 Oct 12. pii: S1535-6108(21)00497-9. [Epub ahead of print]
    Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.
    Joseph M Chan, Álvaro Quintanal-Villalonga, Vianne Ran Gao, Yubin Xie, Viola Allaj, Ojasvi Chaudhary, Ignas Masilionis, Jacklynn Egger, Andrew Chow, Thomas Walle, Marissa Mattar, Dig V K Yarlagadda, James L Wang, Fathema Uddin, Michael Offin, Metamia Ciampricotti, Besnik Qeriqi, Amber Bahr, Elisa de Stanchina, Umesh K Bhanot, W Victoria Lai, Matthew J Bott, David R Jones, Arvin Ruiz, Marina K Baine, Yanyun Li, Natasha Rekhtman, John T Poirier, Tal Nawy, Triparna Sen, Linas Mazutis, Travis J Hollmann, Dana Pe'er, Charles M Rudin.
      Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.
    Keywords:  PLCG2; SCLC; metastasis; myeloid; scRNA-seq; single cell; tumor atlas
    DOI:  https://doi.org/10.1016/j.ccell.2021.09.008
  4. Cancer Discov. 2021 Oct 14.
    Redox Regulation in Cancer Cells during Metastasis.
    Alpaslan Tasdogan, Jessalyn M Ubellacker, Sean J Morrison.
      Metastasis is an inefficient process in which the vast majority of cancer cells are fated to die, partly because they experience oxidative stress. Metastasizing cancer cells migrate through diverse environments that differ dramatically from their tumor of origin, leading to redox imbalances. The rare metastasizing cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We review the changes in redox regulation that cancer cells undergo during metastasis. By better understanding these mechanisms, it may be possible to develop pro-oxidant therapies that block disease progression by exacerbating oxidative stress in cancer cells. SIGNIFICANCE: Oxidative stress often limits cancer cell survival during metastasis, raising the possibility of inhibiting cancer progression with pro-oxidant therapies. This is the opposite strategy of treating patients with antioxidants, an approach that worsened outcomes in large clinical trials.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0558
  5. Theranostics. 2021 ;11(19): 9605-9622
    Visualization of endogenous p27 and Ki67 reveals the importance of a c-Myc-driven metabolic switch in promoting survival of quiescent cancer cells.
    Ting La, Song Chen, Tao Guo, Xiao Hong Zhao, Liu Teng, Dandan Li, Michael Carnell, Yuan Yuan Zhang, Yu Chen Feng, Nicole Cole, Alexandra C Brown, Didi Zhang, Qihan Dong, Jenny Y Wang, Huixia Cao, Tao Liu, Rick F Thorne, Feng-Min Shao, Xu Dong Zhang, Lei Jin.
      Rationale: Recurrent and metastatic cancers often undergo a period of dormancy, which is closely associated with cellular quiescence, a state whereby cells exit the cell cycle and are reversibly arrested in G0 phase. Curative cancer treatment thus requires therapies that either sustain the dormant state of quiescent cancer cells, or preferentially, eliminate them. However, the mechanisms responsible for the survival of quiescent cancer cells remain obscure. Methods: Dual genome-editing was carried out using a CRISPR/Cas9-based system to label endogenous p27 and Ki67 with the green and red fluorescent proteins EGFP and mCherry, respectively, in melanoma cells. Analysis of transcriptomes of isolated EGFP-p27highmCherry-Ki67low quiescent cells was conducted at bulk and single cell levels using RNA-sequencing. The extracellular acidification rate and oxygen consumption rate were measured to define metabolic phenotypes. SiRNA and inducible shRNA knockdown, chromatin immunoprecipitation and luciferase reporter assays were employed to elucidate mechanisms of the metabolic switch in quiescent cells. Results: Dual labelling of endogenous p27 and Ki67 with differentiable fluorescent probes allowed for visualization, isolation, and analysis of viable p27highKi67low quiescent cells. Paradoxically, the proto-oncoprotein c-Myc, which commonly drives malignant cell cycle progression, was expressed at relatively high levels in p27highKi67low quiescent cells and supported their survival through promoting mitochondrial oxidative phosphorylation (OXPHOS). In this context, c-Myc selectively transactivated genes encoding OXPHOS enzymes, including subunits of isocitric dehydrogenase 3 (IDH3), whereas its binding to cell cycle progression gene promoters was decreased in quiescent cells. Silencing of c-Myc or the catalytic subunit of IDH3, IDH3α, preferentially killed quiescent cells, recapitulating the effect of treatment with OXPHOS inhibitors. Conclusion: These results establish a rigorous experimental system for investigating cellular quiescence, uncover the high selectivity of c-Myc in activating OXPHOS genes in quiescent cells, and propose OXPHOS targeting as a potential therapeutic avenue to counter cancer cells in quiescence.
    Keywords:  IDH3; c-Myc; oxidative phosphorylation; quiescence; quiescent cells
    DOI:  https://doi.org/10.7150/thno.63763
  6. Theranostics. 2021 ;11(19): 9705-9720
    Proteomic analysis of lung cancer cells reveals a critical role of BCAT1 in cancer cell metastasis.
    Lin Mao, Jin Chen, Xue Lu, Canlin Yang, Yi Ding, Mingming Wang, Yunpeng Zhang, Yuying Tian, Xing Li, Yunyun Fu, Yueying Yang, Yunyun Gu, Fei Gao, Junxing Huang, Lujian Liao.
      Metastasis is the major cause of high mortality in lung cancer. Exploring the underlying mechanisms of metastasis thus holds promise for identifying new therapeutic strategies that may enhance survival. Methods: We applied quantitative mass spectrometry to compare protein expression profiles between primary and metastatic lung cancer cells whilst investigating metastasis-related molecular features. Results: We discovered that BCAT1, the key enzyme in branched-chain amino acid metabolism, is overexpressed at the protein level in metastatic lung cancer cells, as well as in metastatic tissues from lung cancer patients. Analysis of transcriptomic data available in the TCGA database revealed that increased BCAT1 transcription is associated with poor overall survival of lung cancer patients. In accord with a critical role in metastasis, shRNA-mediated knockdown of BCAT1 expression reduced migration of metastatic cells in vitro and the metastasis of these cells to distal organs in nude mice. Mechanistically, high levels of BCAT1 depleted α-ketoglutarate (α-KG) and promoted expression of SOX2, a transcription factor regulating cancer cell stemness and metastasis. Conclusion: Our findings suggest that BCAT1 plays an important role in promoting lung cancer cell metastasis, and may define a novel pathway to target as an anti-metastatic therapy.
    Keywords:  BCAT1; SOX2; metastasis; stemness
    DOI:  https://doi.org/10.7150/thno.61731
  7. Cancer Discov. 2021 Oct 15.
    Epigenetic Heterogeneity Controls Glioma Cell State and Stress Response.
      DNA methylation alterations facilitate cellular stress response and intratumoral heterogeneity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-147
  8. Cancer Res. 2021 Oct 13. pii: canres.0117.2021. [Epub ahead of print]
    Specific activation of the CD271 intracellular domain in combination with chemotherapy or targeted therapy inhibits melanoma progression.
    Annalisa Saltari, Andreas Dzung, Marika Quadri, Natascia Tiso, Nicola Facchinello, Alberto Hernandez-Barranco, Susana Garcia-Silva, Laura Nogués, Corinne Isabelle Stoffel, Phil F Cheng, Patrick Turko, Ossia M Eichhoff, Francesca Truzzi, Alessandra Marconi, Carlo Pincelli, Héctor Peinado, Reinhard Dummer, Mitchell P Levesque.
      CD271 (NGFR) is a neurotrophin receptor that belongs to the tumor necrosis receptor (TNFR) family. Upon ligand binding, CD271 can mediate either survival or cell death. While the role of CD271 as a marker of tumor-initiating cells is still a matter of debate, its role in melanoma progression has been well documented. Moreover, CD271 has been shown to be upregulated after exposure to both chemotherapy and targeted therapy. In this study, we demonstrate that activation of CD271 by a short β-amyloid-derived peptide (Aβ(25-35)) in combination with either chemotherapy or MAPK inhibitors induces apoptosis in 2D and 3D cultures of 8 melanoma cell lines. This combinatorial treatment significantly reduced metastasis in a zebrafish xenograft model and led to significantly decreased tumor volume in mice. Administration of Aβ(25-35) in ex vivo tumors from immunotherapy- and targeted therapy-resistant patients significantly reduced proliferation of melanoma cells, showing that activation of CD271 can overcome drug resistance. Aβ(25-35) was specific to CD271-expressing cells and induced CD271 cleavage and phosphorylation of JNK (pJNK). The direct protein-protein interaction of pJNK with CD271 led to PARP1 cleavage, p53 and caspase activation, and pJNK-dependent cell death. Aβ(25-35) also mediated mitochondrial reactive oxygen species (mROS) accumulation, which induced CD271 overexpression. Finally, CD271 upregulation inhibited mROS production, revealing the presence of a negative feedback loop in mROS regulation. These results indicate that targeting CD271 can activate cell death pathways to inhibit melanoma progression and potentially overcome resistance to targeted therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0117
  9. Cancer Res. 2021 Oct 15. pii: canres.0980.2021. [Epub ahead of print]
    The HNF4α-BC200-FMR1 positive feedback loop promotes growth and metastasis in invasive mucinous lung adenocarcinoma.
    Xiong Chen, Yujie Zhao, Daxuan Wang, Ying Lin, Jihuan Hou, Xiaolin Xu, Jianben Wu, Linhai Zhong, Yitong Zhou, Jinying Shen, Wenqing Zhang, Hanwei Cao, Xiaoting Hong, Tianhui Hu, Yan-Yan Zhan.
      Invasive mucinous lung adenocarcinoma (IMA) is a subtype of lung adenocarcinoma with a strong invasive ability. IMA frequently carries "undruggable" KRAS mutations, highlighting the need for new molecular targets and therapies. Nuclear receptor HNF4α is abnormally enriched in invasive mucinous lung adenocarcinoma (IMA), but the potential of HNF4α to be a therapeutic target for IMA remains unknown. Here, we report that P2 promoter-driven HNF4α expression promotes IMA growth and metastasis. Mechanistically, HNF4α transactivated lncRNA BC200, which acted as a scaffold for mRNA binding protein FMR1. BC200 promoted the ability of FMR1 to bind and regulate stability of cancer-related mRNAs and HNF4α mRNA, forming a positive feedback circuit. Mycophenolic acid, the active metabolite of FDA-approved drug mycophenolate mofetil, was identified as an HNF4α antagonist exhibiting anti-IMA activities in vitro and in vivo. This study reveals the role of a HNF4α-BC200-FMR1 positive feedback loop in promoting mRNA stability during IMA progression and metastasis, providing a targeted therapeutic strategy for IMA.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0980
  10. Theranostics. 2021 ;11(19): 9571-9586
    The Polo-like kinase 1 inhibitor onvansertib represents a relevant treatment for head and neck squamous cell carcinoma resistant to cisplatin and radiotherapy.
    Anais Hagege, Damien Ambrosetti, Julien Boyer, Alexandre Bozec, Jérôme Doyen, Emmanuel Chamorey, Xingkang He, Isabelle Bourget, Julie Rousset, Esma Saada, Olivia Rastoin, Julien Parola, Frederic Luciano, Yihai Cao, Gilles Pagès, Maeva Dufies.
      Rationale: Head and neck squamous cell carcinoma (HNSCC) represent the 4th most aggressive cancer. 50% of patients relapse to the current treatments combining surgery, radiotherapy and cisplatin and die two years after the diagnosis. Elevated expression of the polo-like kinase 1 (Plk1) correlated to a poor prognosis in epidermoid carcinomas. Methods: The molecular links between Plk1 and resistance to cisplatin/radiotherapy were investigated in patients and cell lines resistant to cisplatin and/or to radiotherapy. The therapeutic relevance of the Plk1 inhibitor onvansertib, alone or combined with cisplatin/radiotherapy, was evaluated on the proliferation/migration on HNSCC cell lines, in experimental HNSCC in mice, in a zebrafish metastasis model and on patient-derived 3D tumor sections. Results: Plk1 expression correlated to a bad prognosis in HNSCC and increased after relapse on cisplatin/radiotherapy. Onvansertib induced mitotic arrest, chromosomic abnormalities and polyploidy leading to apoptosis of sensitive and resistant HNSCC cells at nanomolar concentrations without any effects on normal cells. Onvansertib inhibited the growth of experimental HNSCC in mice and metastatic dissemination in zebrafishes. Moreover, onvansertib combined to cisplatin and/or radiotherapy resulted in a synergic induction of tumor cell death. The efficacy of onvansertib alone and in combination with reference treatments was confirmed on 3D viable sections of HNSCC surgical specimens. Conclusions: Targeting Plk1 by onvansertib represents a new strategy for HNSCC patients at the diagnosis in combination with reference treatments, or alone as a second line treatment for HNCSCC patients experiencing relapses.
    Keywords:  Head and neck squamous cell carcinoma (HNSCC); Plk1; cisplatin resistance; onvansertib; radiation resistance
    DOI:  https://doi.org/10.7150/thno.61711
  11. Theranostics. 2021 ;11(19): 9667-9686
    Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts.
    Pei-Jung Lee, Chao-Chi Ho, Hao Ho, Wan-Jiun Chen, Chiu-Hua Lin, Yi-Hua Lai, Yi-Chen Juan, Wen-Chung Chu, Jia-Hua Lee, Sheng-Fang Su, Hsuan-Yu Chen, Jeremy J W Chen, Gee-Chen Chang, Ker-Chau Li, Pan-Chyr Yang, Huei-Wen Chen.
      The tumorous niche may drive the plasticity of heterogeneity and cancer stemness, leading to drug resistance and metastasis, which is the main reason of treatment failure in most cancer patients. The aim of this study was to establish a tumor microenvironment (TME)-based screening to identify drugs that can specifically target cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs) in the TME. Methods: Lung cancer patient-derived cancer cell and CAFs were utilized to mimic the TME and reproduce the stemness properties of CSCs in vitro and develop a high-throughput drug screening platform with phenotypical parameters. Limiting dilution assay, sphere-forming and ALDH activity assay were utilized to measure the cancer stemness characteristics. In vivo patient-derived xenograft (PDX) models and single-cell RNA sequencing were used to evaluate the mechanisms of the compounds in CSCs and CAFs. Results: The TME-based drug screening platform could comprehensively evaluate the response of cancer cells, CSCs and CAFs to different treatments. Among the 1,524 compounds tested, several drugs were identified to have anti-CAFs, anticancer and anti-CSCs activities. Aloe-emodin and digoxin both show anticancer and anti-CSCs activity in vitro and in vivo, which was further confirmed in the lung cancer PDX model. The combination of digoxin and chemotherapy improved therapeutic efficacy. The single-cell transcriptomics analysis revealed that digoxin could suppress the CSCs subpopulation in CAFs-cocultured cancer cells and cytokine production in CAFs. Conclusions: The TME-based drug screening platform provides a tool to identify and repurpose compounds targeting cancer cells, CSCs and CAFs, which may accelerate drug development and therapeutic application for lung cancer patients.
    Keywords:  Cancer-associated fibroblasts; cancer stem cells; drug screening; high-throughput; tumor microenvironment
    DOI:  https://doi.org/10.7150/thno.62676
  12. Oncogene. 2021 Oct 13.
    A highly annotated database of genes associated with platinum resistance in cancer.
    Dongqing Huang, Sara R Savage, Anna P Calinawan, Chenwei Lin, Bing Zhang, Pei Wang, Timothy K Starr, Michael J Birrer, Amanda G Paulovich.
      Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance develops in a significant number of patients and is a determinant of clinical outcome. Extensive research has been conducted to understand and overcome platinum resistance, and mechanisms of resistance can be categorized into several broad biological processes, including (1) regulation of drug entry, exit, accumulation, sequestration, and detoxification, (2) enhanced repair and tolerance of platinum-induced DNA damage, (3) alterations in cell survival pathways, (4) alterations in pleiotropic processes and pathways, and (5) changes in the tumor microenvironment. As a resource to the cancer research community, we provide a comprehensive overview accompanied by a manually curated database of the >900 genes/proteins that have been associated with platinum resistance over the last 30 years of literature. The database is annotated with possible pathways through which the curated genes are related to platinum resistance, types of evidence, and hyperlinks to literature sources. The searchable, downloadable database is available online at http://ptrc-ddr.cptac-data-view.org .
    DOI:  https://doi.org/10.1038/s41388-021-02055-2
  13. Cell. 2021 Oct 07. pii: S0092-8674(21)01105-3. [Epub ahead of print]
    Spatially confined sub-tumor microenvironments in pancreatic cancer.
    Barbara T Grünwald, Antoine Devisme, Geoffroy Andrieux, Foram Vyas, Kazeera Aliar, Curtis W McCloskey, Andrew Macklin, Gun Ho Jang, Robert Denroche, Joan Miguel Romero, Prashant Bavi, Peter Bronsert, Faiyaz Notta, Grainne O'Kane, Julie Wilson, Jennifer Knox, Laura Tamblyn, Molly Udaskin, Nikolina Radulovich, Sandra E Fischer, Melanie Boerries, Steven Gallinger, Thomas Kislinger, Rama Khokha.
      Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute the human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically definable tissue states anchored in fibroblast plasticity, with regional relationships to tumor immunity, subtypes, differentiation, and treatment response. "Reactive" subTMEs rich in complex but functionally coordinated fibroblast communities were immune hot and inhabited by aggressive tumor cell phenotypes. The matrix-rich "deserted" subTMEs harbored fewer activated fibroblasts and tumor-suppressive features yet were markedly chemoprotective and enriched upon chemotherapy. SubTMEs originated in fibroblast differentiation trajectories, and transitory states were notable both in single-cell transcriptomics and in situ. The intratumoral co-occurrence of subTMEs produced patient-specific phenotypic and computationally predictable heterogeneity tightly linked to malignant biology. Therefore, heterogeneity within the plentiful, notorious pancreatic TME is not random but marks fundamental tissue organizational units.
    Keywords:  cancer-associated fibroblasts; pancreatic cancer; patient-derived organoids; proteomics; stromal heterogeneity; systems biology; treatment resistance; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2021.09.022
  14. Cancer Res. 2021 Oct 13. pii: canres.1825.2021. [Epub ahead of print]
    Targeting KDM6A suppresses SREBP1c-dependent lipid metabolism and prostate tumorigenesis.
    Dong-E Tang, Jia-Xi He, Yong Dai, Hui-Fen Zhou, Cancan Zhang, Qi-Xin Leng, Xinyan Geng, Dexue Fu, Hao-Wu Jiang, Rui Sun, Song-Hui Xu.
      The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer (PCa). Specific homozygous deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the homozygous loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly up-regulated in PCa and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed PCa growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1825
  15. Nat Commun. 2021 Oct 15. 12(1): 6023
    Pathway signatures derived from on-treatment tumor specimens predict response to anti-PD1 blockade in metastatic melanoma.
    Kuang Du, Shiyou Wei, Zhi Wei, Dennie T Frederick, Benchun Miao, Tabea Moll, Tian Tian, Eric Sugarman, Dmitry I Gabrilovich, Ryan J Sullivan, Lunxu Liu, Keith T Flaherty, Genevieve M Boland, Meenhard Herlyn, Gao Zhang.
      Both genomic and transcriptomic signatures have been developed to predict responses of metastatic melanoma to immune checkpoint blockade (ICB) therapies; however, most of these signatures are derived from pre-treatment biopsy samples. Here, we build pathway-based super signatures in pre-treatment (PASS-PRE) and on-treatment (PASS-ON) tumor specimens based on transcriptomic data and clinical information from a large dataset of metastatic melanoma treated with anti-PD1-based therapies as the training set. Both PASS-PRE and PASS-ON signatures are validated in three independent datasets of metastatic melanoma as the validation set, achieving area under the curve (AUC) values of 0.45-0.69 and 0.85-0.89, respectively. We also combine all test samples and obtain AUCs of 0.65 and 0.88 for PASS-PRE and PASS-ON signatures, respectively. When compared with existing signatures, the PASS-ON signature demonstrates more robust and superior predictive performance across all four datasets. Overall, we provide a framework for building pathway-based signatures that is highly and accurately predictive of response to anti-PD1 therapies based on on-treatment tumor specimens. This work would provide a rationale for applying pathway-based signatures derived from on-treatment tumor samples to predict patients' therapeutic response to ICB therapies.
    DOI:  https://doi.org/10.1038/s41467-021-26299-4
  16. Nat Commun. 2021 Oct 11. 12(1): 5930
    Homeostatic membrane tension constrains cancer cell dissemination by counteracting BAR protein assembly.
    Kazuya Tsujita, Reiko Satow, Shinobu Asada, Yoshikazu Nakamura, Luis Arnes, Keisuke Sako, Yasuyuki Fujita, Kiyoko Fukami, Toshiki Itoh.
      Malignancy is associated with changes in cell mechanics that contribute to extensive cell deformation required for metastatic dissemination. We hypothesized that the cell-intrinsic physical factors that maintain epithelial cell mechanics could function as tumor suppressors. Here we show, using optical tweezers, genetic interference, mechanical perturbations, and in vivo studies, that epithelial cells maintain higher plasma membrane (PM) tension than their metastatic counterparts and that high PM tension potently inhibits cancer cell migration and invasion by counteracting membrane curvature sensing/generating BAR family proteins. This tensional homeostasis is achieved by membrane-to-cortex attachment (MCA) regulated by ERM proteins, whose disruption spontaneously transforms epithelial cells into a mesenchymal migratory phenotype powered by BAR proteins. Consistently, the forced expression of epithelial-mesenchymal transition (EMT)-inducing transcription factors results in decreased PM tension. In metastatic cells, increasing PM tension by manipulating MCA is sufficient to suppress both mesenchymal and amoeboid 3D migration, tumor invasion, and metastasis by compromising membrane-mediated mechanosignaling by BAR proteins, thereby uncovering a previously undescribed mechanical tumor suppressor mechanism.
    DOI:  https://doi.org/10.1038/s41467-021-26156-4
  17. Nat Commun. 2021 Oct 12. 12(1): 5955
    Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases.
    Sanjay M Prakadan, Christopher A Alvarez-Breckenridge, Samuel C Markson, Albert E Kim, Robert H Klein, Naema Nayyar, Andrew W Navia, Benjamin M Kuter, Kellie E Kolb, Ivanna Bihun, Joana L Mora, Mia Solana Bertalan, Brian Shaw, Michael White, Alexander Kaplan, Jackson H Stocking, Marc H Wadsworth, Eudocia Q Lee, Ugonma Chukwueke, Nancy Wang, Megha Subramanian, Denisse Rotem, Daniel P Cahill, Viktor A Adalsteinsson, Jeffrey W Miller, Ryan J Sullivan, Scott L Carter, Priscilla K Brastianos, Alex K Shalek.
      Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.
    DOI:  https://doi.org/10.1038/s41467-021-25860-5
  18. PLoS Med. 2021 Oct;18(10): e1003794
    Cancer Special Issue: Early detection and minimal residual disease.
    Beryne Odeny.
      Beryne Odeny discusses PLOS Medicine's Special Issue on early cancer detection and minimal residual disease.
    DOI:  https://doi.org/10.1371/journal.pmed.1003794
  19. Theranostics. 2021 ;11(19): 9415-9430
    Accelerating precision anti-cancer therapy by time-lapse and label-free 3D tumor slice culture platform.
    Fuqiang Xing, Yu-Cheng Liu, Shigao Huang, Xueying Lyu, Sek Man Su, Un In Chan, Pei-Chun Wu, Yinghan Yan, Nana Ai, Jianjie Li, Ming Zhao, Barani Kumar Rajendran, Jianlin Liu, Fangyuan Shao, Heng Sun, Tak Kan Choi, Wenli Zhu, Guanghui Luo, Shuiming Liu, De Li Xu, Kin Long Chan, Qi Zhao, Kai Miao, Kathy Qian Luo, Wei Ge, Xiaoling Xu, Guanyu Wang, Tzu-Ming Liu, Chu-Xia Deng.
      The feasibility of personalized medicine for cancer treatment is largely hampered by costly, labor-intensive and time-consuming models for drug discovery. Herein, establishing new pre-clinical models to tackle these issues for personalized medicine is urgently demanded. Methods: We established a three-dimensional tumor slice culture (3D-TSC) platform incorporating label-free techniques for time-course experiments to predict anti-cancer drug efficacy and validated the 3D-TSC model by multiphoton fluorescence microscopy, RNA sequence analysis, histochemical and histological analysis. Results: Using time-lapse imaging of the apoptotic reporter sensor C3 (C3), we performed cell-based high-throughput drug screening and shortlisted high-efficacy drugs to screen murine and human 3D-TSCs, which validate effective candidates within 7 days of surgery. Histological and RNA sequence analyses demonstrated that 3D-TSCs accurately preserved immune components of the original tumor, which enables the successful achievement of immune checkpoint blockade assays with antibodies against PD-1 and/or PD-L1. Label-free multiphoton fluorescence imaging revealed that 3D-TSCs exhibit lipofuscin autofluorescence features in the time-course monitoring of drug response and efficacy. Conclusion: This technology accelerates precision anti-cancer therapy by providing a cheap, fast, and easy platform for anti-cancer drug discovery.
    Keywords:  3D tumor slice culture; FRET technique; apoptosis; label-free; personalized medicine
    DOI:  https://doi.org/10.7150/thno.59533
  20. Cancer Discov. 2021 Oct 14.
    Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis.
    Raymond Chen, Charles A Ishak, Daniel D De Carvalho.
      Features of the cancer epigenome distinguish cancers from their respective cell of origin and establish therapeutic vulnerabilities that can be exploited through pharmacologic inhibition of DNA- or histone-modifying enzymes. Epigenetic therapies converge with cancer immunotherapies through "viral mimicry," a cellular state of active antiviral response triggered by endogenous nucleic acids often derived from aberrantly transcribed endogenous retrotransposons. This review describes the initial characterization and expansion of viral mimicry-inducing approaches as well as features that "prime" cancers for viral mimicry induction. Increased understanding of viral mimicry in therapeutic contexts suggests potential physiologic roles in cellular homeostasis. SIGNIFICANCE: Recent literature establishes elevated cytosolic double strand RNA (dsRNA) levels as a cancer-specific therapeutic vulnerability that can be elevated by viral mimicry-inducing therapies beyond tolerable thresholds to induce antiviral signaling and increase dependence on dsRNA stress responses mediated by ADAR1. Improved understanding of viral mimicry signaling and tolerance mechanisms reveals synergistic treatment combinations with epigenetic therapies that include inhibition of BCL2, ADAR1, and immune checkpoint blockade. Further characterization of viral mimicry tolerance may identify contexts that maximize efficacy of conventional cancer therapies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0506
  21. Cancer Res. 2021 Oct 13. pii: canres.1572.2021. [Epub ahead of print]
    Hypoxia drives dihydropyrimidine dehydrogenase expression in macrophages and confers chemoresistance in colorectal cancer.
    Marie Malier, Khaldoun Gharzeddine, Marie Helene Laverriere, Sabrina Marsili, Fabienne Thomas, Thomas Decaens, Gaël S Roth, Arnaud Millet.
      Colorectal adenocarcinoma is a leading cause of death worldwide, and immune infiltration in colorectal tumors has been recognized recently as an important pathophysiological event. In this context, tumor-associated macrophages (TAM) have been related to chemoresistance to 5-fluorouracil (5-FU), the first-line chemotherapeutic agent used in treating colorectal cancers. Nevertheless, the details of this chemoresistance mechanism are still poorly elucidated. In the present study, we report that macrophages specifically overexpress dihydropyrimidine dehydrogenase (DPD) in hypoxia, leading to macrophage-induced chemoresistance to 5-FU via inactivation of the drug. Hypoxia-induced macrophage DPD expression was controlled by HIF-2α. TAMs constituted the main contributors to DPD activity in human colorectal primary or secondary tumors while cancer cells did not express significant levels of DPD. Additionally, contrary to humans, macrophages in mice do not express DPD. Together, these findings shed light on the role of TAMs in promoting chemoresistance in colorectal cancers and identify potential new therapeutic targets.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1572
  22. Theranostics. 2021 ;11(19): 9180-9197
    BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators.
    Olivier Castellanet, Fahmida Ahmad, Yaron Vinik, Gordon B Mills, Bianca Habermann, Jean-Paul Borg, Sima Lev, Fabienne Lamballe, Flavio Maina.
      Cell cycle regulators are frequently altered in Triple-Negative Breast Cancer (TNBC). Emerging agents targeting these signals offer the possibility to design new combinatorial therapies. However, preclinical models that recapitulate TNBC primary resistance and heterogeneity are essential to evaluate the potency of these combined treatments. Methods: Bioinformatic processing of human breast cancer datasets was used to analyse correlations between expression levels of cell cycle regulators and patient survival outcome. The MMTV-R26Met mouse model of TNBC resistance and heterogeneity was employed to analyse expression and targeting vulnerability of cell cycle regulators in the presence of BCL-XL blockage. Robustness of outcomes and selectivity was further explored using a panel of human breast cancer cells. Orthotopic studies in nude mice were applied for preclinical evaluation of efficacy and toxicity. Alterations of protein expression, phosphorylation, and/or cellular localisation were analysed by western blots, reverse phase protein array, and immunocytochemistry. Bioinformatics was performed to highlight drug's mechanisms of action. Results: We report that high expression levels of the BCL2L1 gene encoding BCL-XL and of specific cell cycle regulators correlate with poor survival outcomes of TNBC patients. Blockage of BCL-XL confers vulnerability to drugs targeting CDK1/2/4, but not FOXM1, CDK4/6, Aurora A and Aurora B, to all MMTV-R26Met and human TNBC cell lines tested. Combined blockage of BCL-XL and CDK1/2/4 interfered with tumour growth in vivo. Mechanistically, we show that, co-targeting of BCL-XL and CDK1/2/4 synergistically inhibited cell viability by combinatorial depletion of survival and RTK/AKT signals, and concomitantly restoring FOXO3a tumour suppression actions. This was accompanied by an accumulation of DNA damage and consequently apoptosis. Conclusions: Our studies illustrate the possibility to exploit the vulnerability of TNBC cells to CDK1/2/4 inhibition by targeting BCL-XL. Moreover, they underline that specificity matters in targeting cell cycle regulators for combinatorial anticancer therapies.
    Keywords:  BCL-XL; MET; cancer mouse model; cell cycle regulators; triple-negative breast cancer
    DOI:  https://doi.org/10.7150/thno.60503
  23. STAR Protoc. 2021 Dec 17. 2(4): 100792
    Generation of an orthotopic mouse model to study colorectal cancer metastasis.
    Liwen Zhang, Pengcheng Bu.
      This protocol describes the generation of a mouse colorectal cancer (CRC) model to study the mechanism of CRC growth and metastasis. Compared to existing protocols, this protocol is mainly to improve the incidence of metastasis. The major advantage of this model is that it mimics the process of clinical CRC metastasis. Thus, it can be used to study different stages of CRC progression and to identify molecular markers or therapeutic targets. The limitation is the difficulty of performing the operation. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021).
    Keywords:  Cancer; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2021.100792
  24. Trends Cancer. 2021 Oct 06. pii: S2405-8033(21)00193-X. [Epub ahead of print]
    Necroptosis and tumor progression.
    Jiong Yan, Peixing Wan, Swati Choksi, Zheng-Gang Liu.
      Necroptosis, a form of programmed necrotic cell death, is a gatekeeper of host defense against certain pathogen invasions. The deregulation of necroptosis is also a key factor of many inflammatory diseases. Recent studies have revealed an important role of necroptosis in tumorigenesis and metastasis and imply the potential of targeting necroptosis as a novel cancer therapy. While its molecular mechanism has been well studied, details of the regulation and function of necroptosis of tumor cells in tumorigenesis and metastasis only began to emerge recently, and we discuss these herein.
    Keywords:  MLKL; RIPK3; ZBP1; antitumor immunity; metastasis; necroptosis; tumorigenesis
    DOI:  https://doi.org/10.1016/j.trecan.2021.09.003
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