bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–04–11
twenty-two papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Werner helicase is a synthetic-lethal vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy and Immunotherapy.
  2. Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma.
  3. Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation.
  4. Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer.
  5. Breast Cancer Brain Metastases Rely on FASN-Mediated Lipid Biosynthesis.
  6. Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.
  7. Mechanisms of Resistance to KRASG12C-Targeted Therapy.
  8. Myeloid Cell-associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing.
  9. Regulator of calcineurin 1 gene isoform 4 in pancreatic ductal adenocarcinoma regulates the progression of tumor cells.
  10. Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors.
  11. Autophagy and Cancer Dormancy.
  12. Rational Treatment of Metastatic Colorectal Cancer: A Reverse Tale of Men, Mice, and Culture Dishes.
  13. Mechanosurveillance of tumour metastasis.
  14. Pharmacological disruption of the Notch1 transcriptional complex inhibits tumor growth by selectively targeting cancer stem cells.
  15. Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors.
  16. Gut Microbes Create a Liver Premetastatic Niche in Colorectal Cancer.
  17. Squamous cell carcinoma subverts adjacent histologically normal epithelium to promote lateral invasion.
  18. An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.
  19. Creatine promotes cancer metastasis through activation of Smad2/3.
  20. Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment.
  21. SHP2-mediated inhibition of DNA repair contributes to cGAS-STING activation and chemotherapeutic sensitivity in colon cancer.
  22. Adaptive Therapy and the Cost of Drug-Resistant Mutants.
  1. Cancer Discov. 2021 Apr 09. pii: candisc.1508.2020. [Epub ahead of print]
    Werner helicase is a synthetic-lethal vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy and Immunotherapy.
    Gabriele Picco, Chiara Maria Cattaneo, Esmee J van Vliet, Giovanni Crisafulli, Giuseppe Rospo, Sarah Consonni, Sara Filipa Vieira, Inigo Sanchez Rodriguez, Carlotta Cancelliere, Ruby Banerjee, Luuk Johan Schipper, Daniele Oddo, Krijn Kristian Dijkstra, Jindrich Cinatl, Martin Michaelis, Fengtang Yang, Cell Model Network Uk Group, Federica Di Nicolantonio, Andrea Sartore-Bianchi, Salvatore Siena, Sabrina Arena, Emile E Voest, Alberto Bardelli, Mathew J Garnett.
      Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC). The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of immunotherapy patients are refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic-lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR CRC preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in dMMR/MSI-H CRC patients, and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1508
  2. Proc Natl Acad Sci U S A. 2021 Apr 13. pii: e2013598118. [Epub ahead of print]118(15):
    Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma.
    Rana Falahat, Anders Berglund, Ryan M Putney, Patricio Perez-Villarroel, Shota Aoyama, Shari Pilon-Thomas, Glen N Barber, James J Mulé.
      Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell-based immunotherapies. Evidence suggests that activation of stimulator of interferon genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear. In this study, we asked whether this suppression is, in part, epigenetically regulated and whether it is indeed a driver of melanoma resistance to T cell-based immunotherapies. Using genome-wide DNA methylation profiling, we show that promoter hypermethylation of cGAS and STING genes mediates their coordinated transcriptional silencing and contributes to the widespread impairment of the STING signaling function in clinically-relevant human melanomas and melanoma cell lines. This suppression is reversible through pharmacologic inhibition of DNA methylation, which can reinstate functional STING signaling in at least half of the examined cell lines. Using a series of T cell recognition assays with HLA-matched human melanoma tumor-infiltrating lymphocytes (TIL), we further show that demethylation-mediated restoration of STING signaling in STING-defective melanoma cell lines can improve their antigenicity through the up-regulation of MHC class I molecules and thereby enhance their recognition and killing by cytotoxic T cells. These findings not only elucidate the contribution of epigenetic processes and specifically DNA methylation in melanoma-intrinsic STING signaling impairment but also highlight their functional significance in mediating tumor-immune evasion and resistance to T cell-based immunotherapies.
    Keywords:  DNA methylation; STING signaling; antigenicity; epigenetic silencing; immune evasion
    DOI:  https://doi.org/10.1073/pnas.2013598118
  3. Cancer Discov. 2021 Apr 06. pii: candisc.0365.2021. [Epub ahead of print]
    Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation.
    Noritaka Tanaka, Jessica J Lin, Chendi Li, Meagan B Ryan, Junbing Zhang, Lesli A Kiedrowski, Alexa G Michel, Mohammed U Syed, Katerina A Fella, Mustafa Sakhi, Islam Baiev, Dejan Juric, Justin F Gainor, Samuel J Klempner, Jochen K Lennerz, Giulia Siravegna, Liron Bar-Peled, Aaron N Hata, Rebecca S Heist, Ryan B Corcoran.
      Mutant-selective KRASG12C inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in KRASG12C-mutant cancers including non-small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRASG12C inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a KRASG12C NSCLC patient who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (KRAS, NRAS, BRAF, MAP2K1), all of which converge to reactivate RAS-MAPK signaling. Notably, a novel KRASY96D mutation affecting the switch-II pocket, to which MRTX849 and other inactive-state inhibitors bind, was identified that interferes with key protein-drug interactions and confers resistance to these inhibitors in engineered and patient-derived KRASG12C cancer models. Interestingly, a novel, functionally distinct tri-complex KRASG12C active-state inhibitor RM-018 retained the ability to bind and inhibit KRASG12C/Y96D and could overcome resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0365
  4. J Exp Med. 2021 May 03. pii: e20191360. [Epub ahead of print]218(5):
    Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer.
    Allison P Drain, Nastaran Zahir, Jason J Northey, Hui Zhang, Po-Jui Huang, Ori Maller, Johnathon N Lakins, Xinmiao Yu, Jennifer L Leight, Brenda P Alston-Mills, E Shelley Hwang, Yunn-Yi Chen, Catherine C Park, Valerie M Weaver.
      Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.
    DOI:  https://doi.org/10.1084/jem.20191360
  5. Cancer Discov. 2021 Apr 09.
    Breast Cancer Brain Metastases Rely on FASN-Mediated Lipid Biosynthesis.
      Brain metastatic breast tumors depended on lipids produced by fatty acid synthase (FASN) for survival.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-051
  6. Nat Cancer. 2021 Dec;1(12): 1188-1203
    Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.
    Robert M Samstein, Chirag Krishna, Xiaoxiao Ma, Xin Pei, Ken-Wing Lee, Vladimir Makarov, Fengshen Kuo, Jonathan Chung, Raghvendra M Srivastava, Tanaya A Purohit, Douglas R Hoen, Rajarsi Mandal, Jeremy Setton, Wei Wu, Rachna Shah, Besnik Qeriqi, Qing Chang, Sviatoslav Kendall, Lior Braunstein, Britta Weigelt, Pedro Blecua Carrillo Albornoz, Luc G T Morris, Diana L Mandelker, Jorge S Reis-Filho, Elisa de Stanchina, Simon N Powell, Timothy A Chan, Nadeem Riaz.
      Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T cell, natural killer, macrophage, and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2-deficiency on ICB outcome, and have significant implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.
    DOI:  https://doi.org/10.1038/s43018-020-00139-8
  7. Cancer Discov. 2021 Apr 05.
    Mechanisms of Resistance to KRASG12C-Targeted Therapy.
    Neal S Akhave, Amadeo B Biter, David S Hong.
      KRAS mutations are among the most common drivers of human carcinogenesis, and are associated with poor prognosis and an aggressive disease course. With the advent of KRASG12C inhibitors, the RAS protein is now targetable, with such inhibitors showing marked clinical responses across multiple tumor types. However, these responses are short-lived due to the development of resistance. Preclinical studies now suggest MAPK reactivation, stimulation of CDK4/6-dependent cell-cycle transition, and immune defects as possible mechanisms of resistance. Devising strategies to overcome such resistance mechanisms, which are a barrier to long-term clinical response, remain an active area of research. SIGNIFICANCE: Although KRAS-targeted cancer therapy is revolutionary, tumors rapidly develop resistance. Understanding the mechanisms driving this resistance and designing combination strategies to overcome it are integral to achieving long-term disease control.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1616
  8. Clin Cancer Res. 2021 Apr 09.
    Myeloid Cell-associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing.
    Li Wang, John P Sfakianos, Kristin G Beaumont, Guray Akturk, Amir Horowitz, Robert P Sebra, Adam M Farkas, Sacha Gnjatic, Austin Hake, Sudeh Izadmehr, Peter Wiklund, William K Oh, Peter M Szabo, Megan Wind-Rotolo, Keziban Unsal-Kacmaz, Xin Yao, Eric Schadt, Padmanee Sharma, Nina Bhardwaj, Jun Zhu, Matthew D Galsky.
       PURPOSE: To define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer.
    EXPERIMENTAL DESIGN: We pursued an unbiased approach using bulk RNA sequencing data from two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures.
    RESULTS: We identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (Msc2IR) score. Single myeloid phagocytic cells with low Msc2IR scores demonstrated upregulation of proinflammatory cytokines/chemokines and downregulation of antigen presentation genes, were unrelated to M1 versus M2 polarization, and were enriched in pretreatment blood samples from patients with PD-L1 blockade-resistant metastatic urothelial cancer.
    CONCLUSIONS: The balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-4574
  9. Oncogene. 2021 Apr 06.
    Regulator of calcineurin 1 gene isoform 4 in pancreatic ductal adenocarcinoma regulates the progression of tumor cells.
    Mengyi Lao, Xiaozhen Zhang, Tao Ma, Jian Xu, Hanshen Yang, Yi Duan, Honggang Ying, Xiaoyu Zhang, Chengxiang Guo, Junyu Qiu, Xueli Bai, Tingbo Liang.
      Therapeutic strategies to treat pancreatic ductal adenocarcinoma (PDAC) remain unsatisfying and limited. Therefore, it is imperative to fully determine the mechanisms underlying PDAC progression. In the present study, we report a novel role of regulator of calcineurin 1, isoform 4 (RCAN1.4) in regulating PDAC progression. We demonstrated that RCAN1.4 expression was decreased significantly in PDAC tissues compared with that in para-cancerous tissues, and correlated with poor prognosis of patients with pancreatic cancer. In vitro, stable high expression of RCAN1.4 could suppress the metastasis and proliferation and angiogenesis of pancreatic tumor cells. In addition, interferon alpha inducible protein 27 (IFI27) was identified as having a functional role in RCAN1.4-mediated PDAC migration and invasion, while VEGFA play a vital role in RCAN1.4-mediated PDAC angiogenesis. Analysis of mice with subcutaneously/orthotopic implanted xenograft tumors and liver metastasis model confirmed that RCAN1.4 could modulate the growth, metastasis, and angiogenesis of tumors via IFI27/VEGFA in vivo. In conclusion, our results suggested that RCAN1.4 suppresses the growth, metastasis, and angiogenesis of PDAC, functioning partly via IFI27 and VEGFA. Importantly, our results provided possible diagnostic criteria and therapeutic targets for PDAC.
    DOI:  https://doi.org/10.1038/s41388-021-01763-z
  10. Science. 2021 Apr 09. 372(6538): 156-165
    Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors.
    Kasper Fugger, Ilirjana Bajrami, Mariana Silva Dos Santos, Sarah Jane Young, Simone Kunzelmann, Geoff Kelly, Graeme Hewitt, Harshil Patel, Robert Goldstone, Thomas Carell, Simon J Boulton, James MacRae, Ian A Taylor, Stephen C West.
      Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA-deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. BRCA1-deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of BRCA-deficient cancers to PARPi therapy.
    DOI:  https://doi.org/10.1126/science.abb4542
  11. Front Oncol. 2021 ;11 627023
    Autophagy and Cancer Dormancy.
    Yunus Akkoc, Nesibe Peker, Arzu Akcay, Devrim Gozuacik.
      Metastasis and relapse account for the great majority of cancer-related deaths. Most metastatic lesions are micro metastases that have the capacity to remain in a non-dividing state called "dormancy" for months or even years. Commonly used anticancer drugs generally target actively dividing cancer cells. Therefore, cancer cells that remain in a dormant state evade conventional therapies and contribute to cancer recurrence. Cellular and molecular mechanisms of cancer dormancy are not fully understood. Recent studies indicate that a major cellular stress response mechanism, autophagy, plays an important role in the adaptation, survival and reactivation of dormant cells. In this review article, we will summarize accumulating knowledge about cellular and molecular mechanisms of cancer dormancy, and discuss the role and importance of autophagy in this context.
    Keywords:  autophagy; cancer; dormancy; metastasis; recurrence; relapse
    DOI:  https://doi.org/10.3389/fonc.2021.627023
  12. Cancer Discov. 2021 Apr 05.
    Rational Treatment of Metastatic Colorectal Cancer: A Reverse Tale of Men, Mice, and Culture Dishes.
    Marco Avolio, Livio Trusolino.
      Stratification of colorectal cancer into subgroups with different response to therapy was initially guided by descriptive associations between specific biomarkers and treatment outcome. Recently, preclinical models based on propagatable patient-derived tumor samples have yielded an improved understanding of disease biology, which has facilitated the functional validation of correlative information and the discovery of novel response determinants, therapeutic targets, and mechanisms of tumor adaptation and drug resistance. We review the contribution of patient-derived models to advancing colorectal cancer characterization, discuss their influence on clinical decision-making, and highlight emerging challenges in the interpretation and clinical transferability of results obtainable with such approaches. SIGNIFICANCE: Association studies in patients with colorectal cancer have led to the identification of response biomarkers, some of which have been implemented as companion diagnostics for therapeutic decisions. By enabling biological investigation in a clinically relevant experimental context, patient-derived colorectal cancer models have proved useful to examine the causal role of such biomarkers in dictating drug sensitivity and are providing fresh knowledge on new actionable targets, dynamics of tumor evolution and adaptation, and mechanisms of drug resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1531
  13. Nat Rev Immunol. 2021 Apr 07.
    Mechanosurveillance of tumour metastasis.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-021-00546-7
  14. Cancer Res. 2021 Apr 05. pii: canres.CAN-20-3611-A.2020. [Epub ahead of print]
    Pharmacological disruption of the Notch1 transcriptional complex inhibits tumor growth by selectively targeting cancer stem cells.
    Annamil Alvarez-Trotta, William Guerrant, Luisana Astudillo, Mohini Lahiry, Giulia Diluvio, Elena Shersher, Hugo Kaneku, David J Robbins, Darren Orton, Anthony J Capobianco.
      In many human cancers, deregulation of the Notch pathway has been shown to play a role in the initiation and maintenance of the neoplastic phenotype. Aberrant Notch activity also plays a central role in the maintenance and survival of cancer stem cells, which underlie metastasis and resistance to therapy. For these reasons, inhibition of Notch signaling has become an exceedingly attractive target for cancer therapeutic development. However, attempts to develop Notch pathway specific drugs have largely failed in the clinic, in part due to intestinal toxicity. Here we report the discovery of NADI-351, the first specific small molecule inhibitor of Notch1 transcriptional complexes. NADI-351 selectively disrupted Notch1 transcription complexes and reduced Notch1 recruitment to target genes. NADI-351 demonstrated robust anti-tumor activity without inducing intestinal toxicity in mouse models, and cancer stem cells were ablated by NADI-351 treatment. Our study demonstrates that NADI-351 is an orally available and potent inhibitor of Notch1-mediated transcription that inhibits tumor growth with low toxicity, providing a potential therapeutic approach for improved cancer treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3611
  15. Cell Rep. 2021 Apr 06. pii: S2211-1247(21)00258-8. [Epub ahead of print]35(1): 108944
    Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors.
    Roman V Uzhachenko, Vijaya Bharti, Zhufeng Ouyang, Ashlyn Blevins, Stacey Mont, Nabil Saleh, Hunter A Lawrence, Chengli Shen, Sheau-Chiann Chen, Gregory D Ayers, David G DeNardo, Carlos Arteaga, Ann Richmond, Anna E Vilgelm.
      Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.
    Keywords:  CCL5; CDK4/6 inhibitors; ROS; adoptive cell transfer; anti-tumor immunity; cancer metabolism; chemokines; metabolic stress; palbociclib
    DOI:  https://doi.org/10.1016/j.celrep.2021.108944
  16. Cancer Discov. 2021 Apr 09.
    Gut Microbes Create a Liver Premetastatic Niche in Colorectal Cancer.
      Some bacteria disrupted the gut vascular barrier and transit to the liver, where they favored metastasis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-052
  17. J Exp Med. 2021 Jun 07. pii: e20200944. [Epub ahead of print]218(6):
    Squamous cell carcinoma subverts adjacent histologically normal epithelium to promote lateral invasion.
    Priyanka Singh, Rajat Banerjee, Songlin Piao, Marcell Costa de Medeiros, Emily Bellile, Min Liu, Dilna Damodaran Puthiya Veettil, Ligia B Schmitd, Nickole Russo, Erika Danella, Ronald C Inglehart, Kyriel M Pineault, Deneen M Wellik, Greg Wolf, Nisha J D'Silva.
      Recurrent and new tumors, attributed in part to lateral invasion, are frequent in squamous cell carcinomas and lead to poor survival. We identified a mechanism by which cancer subverts adjacent histologically normal epithelium to enable small clusters of cancer cells to burrow undetected under adjacent histologically normal epithelium. We show that suppression of DMBT1 within cancer promotes aggressive invasion and metastasis in vivo and is associated with metastasis in patients. Cancer cells via TGFβ1 and TNFα also suppress DMBT1 in adjacent histologically normal epithelium, thereby subverting it to promote invasion of a small population of tumor cells. The sufficiency of DMBT1 in this process is demonstrated by significantly higher satellite tumor nests in Dmbt1-/- compared with wild-type mice. Moreover, in patients, invasion of small tumor nests under adjacent histologically normal epithelium is associated with increased risk for recurrence and shorter disease-free survival. This study demonstrates a crucial role of adjacent histologically normal epithelium in invasion and its important role in the tumor microenvironment and opens new possibilities for therapeutic strategies that reduce tumor recurrence.
    DOI:  https://doi.org/10.1084/jem.20200944
  18. Elife. 2021 Apr 06. pii: e66788. [Epub ahead of print]10
    An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.
    Rediet Zewdu, Elnaz Mirzaei Mehrabad, Kelley Ingram, Pengshu Fang, Katherine L Gillis, Soledad A Camolotto, Grace Orstad, Alex Jones, Michelle C Mendoza, Benjamin T Spike, Eric L Snyder.
      Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAFV600E driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. NKX2-1-deficient, BRAFV600E driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors. Whereas BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence, NKX2-1-negative cells fail to exit the cell cycle after the same therapy. BRAF/MEK inhibitors induce cell identity switching in NKX2-1-negative lung tumors within the gastric lineage, which is driven in part by WNT signaling and FoxA1/2. These data elucidate a complex, reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of lung adenocarcinoma identity that is likely to impact lineage-specific therapeutic strategies.
    Keywords:  cancer biology; developmental biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.66788
  19. Cell Metab. 2021 Mar 27. pii: S1550-4131(21)00116-9. [Epub ahead of print]
    Creatine promotes cancer metastasis through activation of Smad2/3.
    Liwen Zhang, Zijing Zhu, Huiwen Yan, Wen Wang, Zhenzhen Wu, Fei Zhang, Qixiang Zhang, Guizhi Shi, Junfeng Du, Huiyun Cai, Xuanxuan Zhang, David Hsu, Pu Gao, Hai-Long Piao, Gang Chen, Pengcheng Bu.
      As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.
    Keywords:  GATM; MPS1; SLC6A8; Smad2; Smad3; breast cancer; colorectal cancer; creatine; metastasis
    DOI:  https://doi.org/10.1016/j.cmet.2021.03.009
  20. Gut. 2021 Apr 07. pii: gutjnl-2020-323014. [Epub ahead of print]
    Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment.
    Zhibo Xie, Ya Gao, Chiakang Ho, Lequn Li, Chen Jin, Xiaoyi Wang, Caifeng Zou, Yishen Mao, Xiaobo Wang, Qingfeng Li, Deliang Fu, Yi-Fan Zhang.
       OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) shows a remarkable predilection for liver metastasis. Pro-oncogenic secretome delivery and trafficking via exosomes are crucial for pre-metastatic microenvironment formation and metastasis. This study aimed to explore the underlying mechanisms of how PDAC-derived exosomes (Pex) modulate the liver microenvironment and promote metastasis.
    DESIGN: C57BL/6 mice were 'educated' by tail vein Pex injection. The intrasplenic injection liver metastasis and PDAC orthotopic transplantation models were used to evaluate liver metastasis. Stable cell lines CD44v6 (CD44 variant isoform 6) or C1QBP (complement C1q binding protein) knockdown or overexpression was established using lentivirus transfection or gateway systems. A total of 142 patients with PDAC in Huashan Hospital were retrospectively enrolled. Prognosis and liver metastasis were predicted using Kaplan-Meier survival curves and logistic regression models.
    RESULTS: Pex tail vein injection induced the deposition of liver fibrotic extracellular matrix, which promoted PDAC liver metastasis. Specifically, the exosomal CD44v6/C1QBP complex was delivered to the plasma membrane of hepatic satellite cells (HSCs), leading to phosphorylation of insulin-like growth factor 1 signalling molecules, which resulted in HSC activation and liver fibrosis. Expression of Pex CD44v6 and C1QBP in PDAC patients with liver metastasis was significantly higher than in PDAC patients without liver metastasis, and simultaneous high expression of exosomal CD44v6 and C1QBP correlated with a worse prognosis and a higher risk of postoperative PDAC liver metastasis.
    CONCLUSION: The Pex-derived CD44v6/C1QBP complex is essential for the formation of a fibrotic liver microenvironment and PDAC liver metastasis. Highly expressed exosomal CD44v6 and C1QBP are promising biomarkers for predicting prognosis and liver metastasis in patients with PDAC.
    Keywords:  extracellular matrix; fibrosis; liver metastases; molecular oncology; pancreatic cancer
    DOI:  https://doi.org/10.1136/gutjnl-2020-323014
  21. Cancer Res. 2021 Apr 05. pii: canres.3738.2020. [Epub ahead of print]
    SHP2-mediated inhibition of DNA repair contributes to cGAS-STING activation and chemotherapeutic sensitivity in colon cancer.
    Bin Wei, Lingyan Xu, Wenjie Guo, Yuanyuan Wang, Jingjing Wu, Xiaofei Li, Xiaomin Cai, Jinbo Hu, Meijing Wang, Qiang Xu, Wen Liu, Yanhong Gu.
      As a cytoplasmic sensor of double-stranded DNA (dsDNA), the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an important role in anti-tumor immunity. In this study, we investigated the effect of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) on tumor cell-intrinsic STING pathway activity and DNA repair in colon cancer. SHP2 interacted with and dephosphorylated poly ADP-ribose polymerase (PARP1) after DNA damage. PARP1 inhibition by SHP2 resulted in reduced DNA repair and accumulation of dsDNA in cells, thus promoting hyperactivation of the STING pathway. The SHP2 agonist lovastatin was able to enhance SHP2 activity and promote STING pathway activation. Moreover, lovastatin significantly enhanced the efficacy of chemotherapy in colon cancer models, in part via STING pathway-mediated anti-tumor immunity. These findings suggest that SHP2 exacerbates STING pathway activation by restricting PARP1-mediated DNA repair in tumor cells, providing a basis for the combined use of lovastatin and chemotherapy in the treatment of colon cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3738
  22. Cancer Res. 2021 Feb 15. 81(4): 811-812
    Adaptive Therapy and the Cost of Drug-Resistant Mutants.
    Dominik Wodarz.
      The concept of adaptive cancer therapy proposes that the use of drugs at less than maximum tolerated dose can provide clinical benefits by allowing persisting drug-sensitive cells to competitively suppress drug-resistant cells; this can delay the outgrowth of these cell clones. The adaptive therapy concept has been developed with mathematical models and has subsequently been explored in clinical trials with promising results. In studies performed so far, a fitness cost of drug-resistant cells has been invoked for this treatment approach to be beneficial. In new work, it is shown that a clinical benefit can be achieved even in the absence of a fitness cost for resistant cells, which broadens the applicability of adaptive therapy.See related article by Strobl et al., p. 1135.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-4079
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