bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒11‒15
twenty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Cancer Cell. 2020 Oct 26. pii: S1535-6108(20)30543-2. [Epub ahead of print]
    Guccini I, Revandkar A, D'Ambrosio M, Colucci M, Pasquini E, Mosole S, Troiani M, Brina D, Sheibani-Tezerji R, Elia AR, Rinaldi A, Pernigoni N, Rüschoff JH, Dettwiler S, De Marzo AM, Antonarakis ES, Borrelli C, Moor AE, Garcia-Escudero R, Alajati A, Attanasio G, Losa M, Moch H, Wild P, Egger G, Alimonti A.
      Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor TIMP1 as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by PTEN deficiency or chemotherapy limits the progression of prostate cancer in mice. TIMP1 deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of PTEN and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.
    Keywords:  FGF1; GDF-15; MMPs; PTEN; TIMP1; docetaxel; prostate cancer metastasis; senescence; senescence-associated secretory phenotype (SASP); senolytic therapy
  2. Cancer Res. 2020 Nov 10. pii: canres.1693.2020. [Epub ahead of print]
    Tagal V, Roth MG.
      Polyploid giant cancer cells (PGCC) are common in tumors and have been associated with resistance to cancer therapy, tumor relapse, malignancy, immunosuppression, metastasis, cancer stem cell production, and modulation of the tumor microenvironment. However, the molecular mechanisms that cause these cells to form are not yet known. In this study, we discover that Aurora kinases are synergistic determinants of a switch from the proliferative cell cycle to polyploid growth and multinucleation in lung cancer cell lines. When Aurora kinases were inhibited together, lung cancer cells uniformly grew into multinucleated polyploid giant cancer cells. These cells adopted an endoreplication in which the genome replicates, mitosis is omitted, and cells grow in size. Consequently, such cells continued to safely grow in the presence of antimitotic agents. These PGCC re-entered the proliferative cell cycle and grew in cell number when treatment was terminated. Thus, PGCC formation might represent a fundamental cellular response to Aurora kinase inhibitors and contribute to therapy resistance or tumor relapse.
  3. Cancer Res. 2020 Nov 10. pii: canres.1488.2020. [Epub ahead of print]
    Wang Y, Zhao G, Condello S, Huang H, Cardenas H, Tanner EJ, Wei J, Ji Y, Li J, Tan Y, Davuluri RV, Peter ME, Cheng JX, Matei D.
      Defining traits of platinum-tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum-tolerant cells and tumors were identified using in vitro and in vivo ovarian cancer (OC) models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were enriched in ALDH (+) cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared to parental cells. Additionally, platinum-tolerant cells and tumors exhibited expression of the Wnt receptor Frizzled 7 (FZD7). Knockdown of FZD7 improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7(+) from FZD7(-) cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation-enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protected cells from chemotherapy-induced oxidative stress. FZD7(+) platinum-tolerant OC cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63, and glutathione metabolism gene sets were strongly correlated in the OC Tumor Cancer Genome Atlas (TCGA) database and in human OC specimens residual after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial stem cell features, characterized by FZD7 expression and dependent on FZD7-β-catenin-Tp63-GPX4 pathway for survival. These findings reveal a novel therapeutic vulnerability of platinum-tolerant cancer cells and provide new insight into a potential "persister cancer cell" phenotype.
  4. Cancer Res. 2020 Nov 15. 80(22): 4886-4887
    Man J, Pajic M, Joshua AM.
      In this issue of Cancer Research, Rozeveld and colleagues present intriguing evidence of the importance of lipid droplets and hormone-sensitive lipase (HSL) in regulating the aggressive nature of pancreatic cancer. Initially demonstrating a dependency of preloaded lipids on an invasive phenotype, the authors then establish that oncogenic KRAS mutation downregulates HSL, thereby facilitating lipid storage during steady state. Thereafter, a phenotypic switch to oxidative metabolism with lipid utilization to fuel invasion and metastasis occurs. Experimentally, blocking the KRAS-HSL axis results in fewer lipid droplets, as well as metabolic reprogramming of the invasive cell phenotype, effectively reducing invasive capacity of KRAS-mutant pancreatic cancer. Of note, HSL overexpression in tumor cells also inhibited invasion, due to depletion of lipid droplets and the stored lipids, which are essential during invasion. Collectively, these novel findings highlight the importance of energy metabolism and its dynamic regulation in the evolution of the metastatic capacity of pancreatic cancer.See related article by Rozeveld et al., p. 4932.
  5. Cancer Res. 2020 Nov 10. pii: canres.0256.2020. [Epub ahead of print]
    Geng Y, Fan J, Chen L, Zhang C, Qu C, Qian L, Chen K, Meng Z, Chen Z, Wang P.
      Notch activation has been detected in pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC metastasis remains unknown. In this study, we identify a Notch-dependent feedback circuit between pancreatic cancer cells and macrophages which contributes to PDAC metastasis. In this circuit, miR-124 regulated Notch signaling in cancer cells by directly targeting the Notch ligand Jagged 1 (JAG1). Auto-amplified Notch signaling promoted the recruitment and activation of macrophages to a tumor-supporting M2-like phenotype via downstream interleukin (IL)-8, CCL2, IL-1α, and uPA paracrine signaling. In turn, activated macrophage-derived IL-6 activated the oncogenic transcription factor STAT3 that directly repressed miR-124 genes via a conserved STAT3-binding site in their promoters, thereby promoting cancer cell EMT and invasion. Disrupting this circuit suppressed liver metastasis in mouse models. Thus, our study suggests that manipulation of this Notch-dependent circuit has a therapeutic potential for the treatment of PDAC metastasis.
  6. Cell Mol Life Sci. 2020 Nov 10.
    Liu T, Han C, Fang P, Zhu H, Wang S, Ma Z, Zhang Q, Xia W, Wang J, Xu L, Yin R.
      The efficacy of targeted therapy in non-small-cell lung cancer (NSCLC) has been impeded by various mechanisms of resistance. Besides the mutations in targeted oncogenes, reversible lineage plasticity has recently considered to play a role in the development of tyrosine kinase inhibitors (TKI) resistance in NSCLC. Lineage plasticity enables cells to transfer from one committed developmental pathway to another, and has been a trigger of tumor adaptation to adverse microenvironment conditions including exposure to various therapies. More importantly, besides somatic mutation, lineage plasticity has also been proposed as another source of intratumoural heterogeneity. Lineage plasticity can drive NSCLC cells to a new cell identity which no longer depends on the drug-targeted pathway. Histological transformation and epithelial-mesenchymal transition are two well-known pathways of lineage plasticity-mediated TKI resistance in NSCLC. In the last decade, increased re-biopsy practice upon disease recurrence has increased the recognition of lineage plasticity induced resistance in NSCLC and has improved our understanding of the underlying biology. Long non-coding RNAs (lncRNAs), the dark matter of the genome, are capable of regulating variant malignant processes of NSCLC like the invisible hands. Recent evidence suggests that lncRNAs are involved in TKI resistance in NSCLC, particularly in lineage plasticity-mediated resistance. In this review, we summarize the mechanisms of lncRNAs in regulating lineage plasticity and TKI resistance in NSCLC. We also discuss how understanding these themes can alter therapeutic strategies, including combination therapy approaches to overcome TKI resistance.
    Keywords:  Lineage plasticity; Long non-coding RNAs; Non-small-cell lung cancer; Tyrosine kinase inhibitors
  7. Cancer Res. 2020 Nov 10. pii: canres.2612.2020. [Epub ahead of print]
    Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano L.
      In many tumors, cells transition reversibly between slow-proliferating tumor-initiating cells (TIC) and their differentiated, faster-growing progeny. Yet how transcriptional regulation of cell cycle and self-renewal genes is orchestrated during these conversions remains unclear. In this study, we show that as breast TIC form, a decrease in cell-cycle and increase in self-renewal gene expression is coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long non-coding RNA (lncRNA) that we name SCIRT, which was markedly upregulated in tumorspheres but colocalized with and counteracted EZH2 and SOX2 during cell cycle and self-renewal regulation to restrain tumorigenesis. SCIRT specifically interacted with EZH2 to increase EZH2 affinity to FOXM1 without binding the latter. In this manner, SCIRT induced transcription at cell cycle gene promoters by recruiting FOXM1 through EZH2 to antagonize EZH2-mediated effects at target genes. Conversely, on stemness genes, FOXM1 was absent and SCIRT antagonized EZH2 and SOX2 activity, balancing towards repression. These data suggest that the interaction of a lncRNA with EZH2 can alter the affinity of EZH2 for its protein binding partners to regulate cancer cell state transitions.
  8. Mol Cancer Res. 2020 Nov 10. pii: molcanres.0414.2020. [Epub ahead of print]
    Ramkumar K, Stewart CA, Cargill KR, Della Corte CM, Wang Q, Shen L, Diao L, Cardnell RJ, Peng DH, Rodriguez BL, Fan YH, Heymach JV, Wang J, Gay CM, Gibbons DL, Byers LA.
      AXL, a TAM family receptor tyrosine kinase, is increasingly being recognized as a key determinant of resistance to targeted therapies as well as chemotherapy and radiation in non-small cell lung cancer (NSCLC) and other cancers. We further show here that high levels of AXL and EMT were frequently expressed in subsets of both treatment-naïve and treatment-relapsed NSCLC. Previously, we and others have demonstrated a role for AXL in mediating DNA damage repair (DDR) as well as resistance to inhibition of WEE1, a replication stress response kinase. Here, we show that BGB324 (bemcentinib), a selective small-molecule AXL inhibitor, caused DNA damage and induced replication stress, indicated by ATR/CHK1 phosphorylation, more significantly in TP53-deficient NSCLC cell lines. Similar effects were also observed in large cell neuroendocrine carcinoma (LCNEC) cell lines. High AXL protein levels were also associated with resistance to ATR inhibition. Combined inhibition of AXL and ATR significantly decreased cell proliferation of NSCLC and LCNEC cell lines. Mechanistically, combined inhibition of AXL and ATR significantly increased RPA32 hyper-phosphorylation and DNA double strand breaks and induced markers of mitotic catastrophe. Notably, NSCLC cell lines with low levels of SLFN11, a known predictive biomarker for platinum and PARP inhibitor sensitivity, were more sensitive to AXL/ATR co-targeting. These findings demonstrate a novel and unexpected role for AXL in replication stress tolerance, with potential therapeutic implications. Implications: These findings demonstrate that the combination of AXL and ATR inhibitors could be a promising therapeutic combination for NSCLC, LCNEC and other cancers.
  9. Clin Cancer Res. 2020 Nov 10. pii: clincanres.2861.2020. [Epub ahead of print]
    Guo R, Offin M, Brannon AR, Chang JC, Chow A, Delasos L, Girshman J, Wilkins O, McCarthy CG, Makhnin A, Falcon CJ, Scott K, Tian Y, Cecchi F, Hembrough T, Alex D, Shen R, Benayed R, Li BT, Rudin CM, Kris MG, Arcila ME, Rekhtman N, Paik PK, Zehir A, Drilon A.
      PURPOSE: MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in MET exon 14-altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed.EXPERIMENTAL DESIGN: We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, mass spectrometry (SRM-MS), and immunohistochemistry (IHC) on patient samples of MET exon 14-altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression free survival (PFS), and putative genomic alterations and MET protein expression were evaluated.
    RESULTS: Seventy-five of 168 MET exon 14-altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole genome duplication) and known (copy number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS (P > 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS (N = 15) or IHC (N = 22) responded to MET TKI therapy, and cancers with H-score > 200 had a higher PFS than cancers below this cutoff (10.4 vs 5.5 months, respectively; hazard ratio 3.87, P = 0.02).
    CONCLUSIONS: In MET exon 14-altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials.
  10. Cancer Res. 2020 Nov 12. pii: canres.1602.2020. [Epub ahead of print]
    Panzarino NJ, Krais JJ, Cong K, Peng M, Mosqueda M, Nayak SU, Bond SM, Calvo JA, Doshi MB, Bere M, Ou J, Deng B, Zhu LJ, Johnson N, Cantor SB.
      Defects in DNA repair and the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes BRCA1 and BRCA2 (BRCA). Challenging this assumption are recent findings that indicate chemotherapies such as cisplatin used to treat BRCA-deficient tumors do not initially cause DNA double-strand-breaks (DSB). Here we show that single-stranded DNA (ssDNA) replication gaps underlie the hypersensitivity of BRCA-deficient cancer and that defects in homologous recombination (HR) or fork protection (FP) do not. In BRCA-deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR could be uncoupled from therapy resistance when gaps were present. Moreover, DSB were not detected after therapy when apoptosis was inhibited, supporting a framework in which DSB are not directly induced by genotoxic agents, but rather are induced from cell death nucleases and are not fundamental to the mechanism of action of genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, "BRCAness," and we propose they are fundamental to the mechanism-of-action of genotoxic chemotherapies.
  11. Proc Natl Acad Sci U S A. 2020 Nov 09. pii: 202016270. [Epub ahead of print]
    Sajid A, Lusvarghi S, Murakami M, Chufan EE, Abel B, Gottesman MM, Durell SR, Ambudkar SV.
      P-glycoprotein (P-gp), also known as ABCB1, is a cell membrane transporter that mediates the efflux of chemically dissimilar amphipathic drugs and confers resistance to chemotherapy in most cancers. Homologous transmembrane helices (TMHs) 6 and 12 of human P-gp connect the transmembrane domains with its nucleotide-binding domains, and several residues in these TMHs contribute to the drug-binding pocket. To investigate the role of these helices in the transport function of P-gp, we substituted a group of 14 conserved residues (seven in both TMHs 6 and 12) with alanine and generated a mutant termed 14A. Although the 14A mutant lost the ability to pump most of the substrates tested out of cancer cells, surprisingly, it acquired a new function. It was able to import four substrates, including rhodamine 123 (Rh123) and the taxol derivative flutax-1. Similar to the efflux function of wild-type P-gp, we found that uptake by the 14A mutant is ATP hydrolysis-, substrate concentration-, and time-dependent. Consistent with the uptake function, the mutant P-gp also hypersensitizes HeLa cells to Rh123 by 2- to 2.5-fold. Further mutagenesis identified residues from both TMHs 6 and 12 that synergistically form a switch in the central region of the two helices that governs whether a given substrate is pumped out of or into the cell. Transforming P-gp or an ABC drug exporter from an efflux transporter into a drug uptake pump would constitute a paradigm shift in efforts to overcome cancer drug resistance.
    Keywords:  ABC transporter; P-glycoprotein; drug transport; mechanism; multidrug resistance
  12. Cancer Cell. 2020 Oct 23. pii: S1535-6108(20)30540-7. [Epub ahead of print]
    Han J, Yu M, Bai Y, Yu J, Jin F, Li C, Zeng R, Peng J, Li A, Song X, Li H, Wu D, Li L.
      Ependymoma is the third most common pediatric tumor with posterior fossa group A (PFA) being its most aggressive subtype. Ependymomas are generally refractory to chemotherapies and thus lack any effective treatment. Here, we report that elevated expression of CXorf67 (chromosome X open reading frame 67), which frequently occurs in PFA ependymomas, suppresses homologous recombination (HR)-mediated DNA repair. Mechanistically, CXorf67 interacts with PALB2 and inhibits PALB2-BRCA2 interaction, thereby inhibiting HR repair. Concordantly, tumor cells with high CXorf67 expression levels show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with radiotherapy. Thus, our findings have revealed a role of CXorf67 in HR repair and suggest that combination of PARP inhibitors with radiotherapy could be an effective treatment option for PFA ependymomas.
    Keywords:  CXorf67; PALB2; PARP inhibitors; ependymoma tumor; homologous recombination repair; radiotherapy
  13. Cancers (Basel). 2020 Nov 06. pii: E3280. [Epub ahead of print]12(11):
    Heidegger I.
      In recent years, the treatment landscape of advanced prostate cancer has radically changed [...].
    Keywords:  biomarker; metastatic castration-resistant prostate cancer; metastatic hormone-sensitive prostate cancer; personalized therapy
  14. Cancer Res. 2020 Nov 10. pii: canres.0806.2020. [Epub ahead of print]
    Strobl MAR, West J, Viossat Y, Damaghi M, Robertson-Tessi M, Brown JS, Gatenby RA, Maini PK, Anderson ARA.
      Adaptive therapy seeks to exploit intra-tumoral competition to avoid, or at least delay, the emergence of therapy resistance in cancer. Motivated by promising results in prostate cancer, there is growing interest in extending this approach to other neoplasms. As such, it is urgent to understand the characteristics of a cancer which determine whether or not it will respond well to adaptive therapy. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this paper, we study a general but simple mathematical model to investigate whether the presence of a cost is necessary for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. Tumor cells were divided into sensitive and resistant populations and we model their competition using a system of two ordinary differential equations based on the Lotka-Volterra model. For tumors close to their environmental carrying capacity a cost was not required. However, for tumors growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, it is important to consider cell turnover in the tumor, and we discuss its role in modulating the impact of a resistance cost. To conclude, we present evidence for the predicted cost-turnover interplay in data from 67 prostate cancer patients undergoing intermittent androgen deprivation therapy. Our work helps to clarify under which circumstances adaptive therapy may be beneficial and suggests that turnover may play an unexpectedly important role in the decision making process.
  15. Cancers (Basel). 2020 Nov 08. pii: E3299. [Epub ahead of print]12(11):
    Contarelli S, Fedele V, Melisi D.
      Angiogenesis is one of the hallmarks of cancer, and the inhibition of pro-angiogenic factors and or their receptors has become a primary strategy for cancer therapy. However, despite promising results in preclinical studies, the majority of patients either do not respond to these treatments or, after an initial period of response, they develop resistance to anti-angiogenic agents. Thus, the identification of a novel therapeutic target is urgently needed. Multiple mechanisms of resistance to anti-angiogenic therapy have been identified, including the upregulation of alternative angiogenic pathways and the recruitment of pro-angiogenic myeloid cells in the tumor microenvironment. Homeobox containing (HOX) genes are master regulators of embryonic development playing a pivotal role during both embryonic vasculogenesis and pathological angiogenesis in adults. The importance of HOX genes during cancer progression has been reported in many studies. In this review we will give a brief description of the HOX genes and their involvement in angiogenesis and cancer, with particular emphasis on HOXB9 as a possible novel target for anti-angiogenic therapy. HOXB9 upregulation has been reported in many types of cancers and it has been identified as a critical transcription factor involved in resistance to anti-angiogenic drugs.
    Keywords:  HOXB9; angiogenesis; anti-angiogenic therapy; therapeutic resistance
  16. Cell. 2020 Nov 12. pii: S0092-8674(20)31391-X. [Epub ahead of print]183(4): 860-874
    Shen S, Vagner S, Robert C.
      Persistent cancer cells are the discrete and usually undetected cells that survive cancer drug treatment and constitute a major cause of treatment failure. These cells are characterized by their slow proliferation, highly flexible energy consumption, adaptation to their microenvironment, and phenotypic plasticity. Mechanisms that underlie their persistence offer highly coveted and sought-after therapeutic targets, and include diverse epigenetic, transcriptional, and translational regulatory processes, as well as complex cell-cell interactions. Although the successful clinical targeting of persistent cancer cells remains to be realized, immense progress has been made in understanding their persistence, yielding promising preclinical results.
    Keywords:  adaptive resistance; cancer drug addiction; cancer treatment; mechanisms of cancer persistence; non-genetic resistance; persistent cancer cells; therapeutic evasion
  17. Cancer Res. 2020 Nov 12. pii: canres.1200.2020. [Epub ahead of print]
    Williams MM, Spoelstra NS, Arnesen S, O'Neill KI, Christenson JL, Reese J, Torkko KC, Goodspeed A, Rosas E, Hanamura T, Sams SB, Li Z, Oesterreich S, Riggins RB, Jacobsen BM, Elias A, Gertz J, Richer JK.
      Mutations in ESR1 that confer constitutive estrogen receptor alpha (ER) activity in the absence of ligand are acquired by ≥40% of metastatic breast cancers (MBC) resistant to adjuvant aromatase inhibitor (AI) therapy. To identify targetable vulnerabilities in MBC, we examined steroid hormone receptors and tumor-infiltrating immune cells in metastatic lesions with or without ER mutations. ER and progesterone receptor (PR) were significantly lower in metastases with wild type (WT) ER compared to those with mutant ER, suggesting that metastases that evade AI therapy by mechanism(s) other than acquiring ER mutations lose dependency on ER and PR. Metastases with mutant ER had significantly higher T regulatory and T helper cells, total macrophages, and PD-L1 positive immune-suppressive macrophages than those with WT ER. BC cells with CRISPR Cas9-edited ER (D538G, Y537S, or WT) and patient-derived xenografts (PDX) harboring mutant or WT ER revealed genes and proteins elevated in mutant ER cells, including androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and interferon-stimulated genes (ISG). Targeting these proteins blunted the selective advantage of ER mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard of care fulvestrant or other selective estrogen receptor degraders (SERD) when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy.
  18. Cancers (Basel). 2020 Nov 05. pii: E3269. [Epub ahead of print]12(11):
    Garcia-Mayea Y, Mir C, Carballo L, Castellvi J, Temprana-Salvador J, Lorente J, Benavente S, García-Pedrero JM, Allonca E, Rodrigo JP, LLeonart ME.
      Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial-mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 with EMT and metastasis. Immunohistochemical analysis of HNSCC specimens further revealed that TSPAN1 expression was correlated with phospho-SRC (pSRC), and inversely with E-cadherin, thus reinforcing TSPAN1 association with EMT. Overall, TSPAN1 emerges as a novel oncogenic protein and a promising target for HNSCC therapy.
    Keywords:  HNSCC; apoptosis; autophagy; cancer; cancer stem cells; resistance
  19. Clin Cancer Res. 2020 Nov 10. pii: clincanres.2769.2020. [Epub ahead of print]
    Liu CC, Veeraraghavan J, Tan Y, Kim JA, Wang X, Loo SK, Lee S, Hu Y, Wang XS.
      PURPOSE: Luminal B breast tumors are more aggressive estrogen receptor positive breast cancers characterized by aggressive clinical behavior and a high risk of metastatic dissemination. The underlying pathological molecular events remain poorly understood with a paucity of actionable genetic drivers, which hinders the development of new treatment strategies.EXPERIMENTAL DESIGN: We performed large-scale RNAseq analysis to identify chimerical transcripts preferentially expressed in luminal B breast cancer. The lead candidate was validated by Reverse Transcription PCR in breast cancer tissues. The effects of inducible ectopic expression or genetic silencing were assessed by phenotypic assays such as MTS, transwell and transendothelial migration assays, and by clonogenic assays to assess MEK inhibitor sensitivity. Subcellular fractionation, western blots, and immunoprecipitation were performed to characterize the protein products and elucidate the engaged mechanisms.
    RESULTS: Here we report a novel tumor-specific chimeric transcript RAD51AP1-DYRK4 preferentially expressed in luminal B tumors. Analysis of 200 ER-positive breast tumors detected RAD51AP1-DYRK4 overexpression in 19 tumors (9.5%), which is markedly enriched in the luminal B tumors (17.5%). Ectopic expression of RAD51AP1-DYRK4, but not wild-type RAD51AP1, leads to marked activation of MEK/ERK signaling, and endows increased cell motility and transendothelial migration. More importantly, RAD51AP1-DYRK4 appears to endow increased sensitivity to the MEK inhibitor Trametinib through attenuating compensatory activation of HER2/PI3K/AKT under MEK inhibition.
    CONCLUSIONS: This discovery sheds light on a new area of molecular pathobiology of luminal B tumors and implies potential new therapeutic opportunities for more aggressive breast tumors overexpressing this fusion.