bims-tucedo 2022-06-26 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2022‒06‒26
twenty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

Mapping Phenotypic Plasticity upon the Cancer Cell State Landscape Using Manifold Learning.
Harnessing redox signaling to overcome therapeutic-resistant cancer dormancy.
Treatment represents a key driver of metastatic cancer evolution.
The metastatic spread of breast cancer accelerates during sleep.
Lymph node metastasis fuels systemic disease.
Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer.
Resistance to BRAF/MEK Inhibition in Melanoma Is Mediated by the Androgen Receptor.
Poziotinib inhibits HER2 mutant-driven therapeutic resistance and multi-organ metastasis in breast cancer.
Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma.
OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma.
circEXOC6B interacting with RRAGB, an mTORC1 activator, inhibits the progression of colorectal cancer by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop.
IL6 Signaling Enables Survival of Chromosomally Instable Cancer Cells.
Cancer-associated fibroblasts suppress CD8+ T cell infiltration and confer resistance to immune checkpoint blockade.
Endothelial p130cas confers resistance to anti-angiogenesis therapy.
HAO1-mediated oxalate metabolism promotes lung pre-metastatic niche formation by inducing neutrophil extracellular traps.
Cancer cells spread aggressively during sleep.
KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy.
BCG hydrogel promotes CTSS-mediated antigen processing and presentation, thereby suppressing metastasis and prolonging survival in melanoma.
DLGAP1-AS2-Mediated Phosphatidic Acid Synthesis Activates YAP Signaling and Confers Chemoresistance in Squamous Cell Carcinoma.
Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas.

Cancer Discov. 2022 Jun 23. OF1-OF13

Mapping Phenotypic Plasticity upon the Cancer Cell State Landscape Using Manifold Learning.

Daniel B Burkhardt, Beatriz P San Juan, John G Lock, Smita Krishnaswamy, Christine L Chaffer.

Phenotypic plasticity describes the ability of cancer cells to undergo dynamic, nongenetic cell state changes that amplify cancer heterogeneity to promote metastasis and therapy evasion. Thus, cancer cells occupy a continuous spectrum of phenotypic states connected by trajectories defining dynamic transitions upon a cancer cell state landscape. With technologies proliferating to systematically record molecular mechanisms at single-cell resolution, we illuminate manifold learning techniques as emerging computational tools to effectively model cell state dynamics in a way that mimics our understanding of the cell state landscape. We anticipate that "state-gating" therapies targeting phenotypic plasticity will limit cancer heterogeneity, metastasis, and therapy resistance.SIGNIFICANCE: Nongenetic mechanisms underlying phenotypic plasticity have emerged as significant drivers of tumor heterogeneity, metastasis, and therapy resistance. Herein, we discuss new experimental and computational techniques to define phenotypic plasticity as a scaffold to guide accelerated progress in uncovering new vulnerabilities for therapeutic exploitation.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0282
Biochim Biophys Acta Rev Cancer. 2022 Jun 15. pii: S0304-419X(22)00074-9. [Epub ahead of print]1877(4): 188749

Harnessing redox signaling to overcome therapeutic-resistant cancer dormancy.

Siyuan Qin, Bowen Li, Hui Ming, Edouard C Nice, Bingwen Zou, Canhua Huang.

  Dormancy occurs when cells preserve viability but stop proliferating, which is considered an important cause of tumor relapse, which may occur many years after clinical remission. Since the life cycle of dormant cancer cells is affected by both intracellular and extracellular factors, gene mutation or epigenetic regulation of tumor cells may not fully explain the mechanisms involved. Recent studies have indicated that redox signaling regulates the formation, maintenance, and reactivation of dormant cancer cells by modulating intracellular signaling pathways and the extracellular environment, which provides a molecular explanation for the life cycle of dormant tumor cells. Indeed, redox signaling regulates the onset of dormancy by balancing the intrinsic pathways, the extrinsic environment, and the response to therapy. In addition, redox signaling sustains dormancy by managing stress homeostasis, maintaining stemness and immunogenic equilibrium. However, studies on dormancy reactivation are still limited, partly explained by redox-mediated activation of lipid metabolism and the transition from the tumor microenvironment to inflammation. Encouragingly, several drug combination strategies based on redox biology are currently under clinical evaluation. Continuing to gain an in-depth understanding of redox regulation and develop specific methods targeting redox modification holds the promise to accelerate the development of strategies to treat dormant tumors and benefit cancer patients.

Keywords:  Cancer therapy; Dormancy; Drug resistance; ROS; Redox signaling

DOI:  https://doi.org/10.1016/j.bbcan.2022.188749
Cancer Res. 2022 Jun 22. pii: canres.CAN-22-0562-E.2022. [Epub ahead of print]

Treatment represents a key driver of metastatic cancer evolution.

Ditte Sigaard Christensen, Johanne Ahrenfeldt, Mateo Sokač, Judit Kisistók, Martin K Thomsen, Lasse Maretty, Nicholas McGranahan, Nicolai J Birkbak.

Metastasis is the main cause of cancer death, yet the evolutionary processes behind it remain largely unknown. Here, through analysis of large panel-based genomic datasets from the AACR GENIE project, including 40,979 primary and metastatic tumors across 25 distinct cancer types, we explore how the evolutionary pressure of cancer metastasis shapes the selection of genomic drivers of cancer. The most commonly affected genes were TP53, MYC, and CDKN2A, with no specific pattern associated with metastatic disease. This suggests that, on a driver mutation level, the selective pressure operating in primary and metastatic tumors is similar. The most highly enriched individual driver mutations in metastatic tumors were mutations known to drive resistance to hormone therapies in breast and prostate cancer (ESR1 and AR), anti-EGFR therapy in non-small cell lung cancer (EGFR T790M), and imatinib in gastrointestinal cancer (KIT V654A). Specific mutational signatures were also associated with treatment in three cancer types, supporting clonal selection following anti-cancer therapy. Overall, this implies that initial acquisition of driver mutations is predominantly shaped by the tissue of origin, where specific mutations define the developing primary tumor and drive growth, immune escape, and tolerance to chromosomal instability. However, acquisition of driver mutations that contribute to metastatic disease is less specific, with the main genomic drivers of metastatic cancer evolution associating with resistance to therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0562
Nature. 2022 Jun 22.

The metastatic spread of breast cancer accelerates during sleep.

Zoi Diamantopoulou, Francesc Castro-Giner, Fabienne Dominique Schwab, Christiane Foerster, Massimo Saini, Selina Budinjas, Karin Strittmatter, Ilona Krol, Bettina Seifert, Viola Heinzelmann-Schwarz, Christian Kurzeder, Christoph Rochlitz, Marcus Vetter, Walter Paul Weber, Nicola Aceto.

The metastatic spread of cancer is achieved by the haematogenous dissemination of circulating tumour cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, and it is often assumed that CTCs are constantly shed from growing tumours or are shed as a consequence of mechanical insults1. Here we observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that most spontaneous CTC intravasation events occur during sleep. Further, we demonstrate that rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability. Mechanistically, single-cell RNA sequencing analysis of CTCs reveals a marked upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Systemically, we find that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictate CTC generation dynamics, and as a consequence, that insulin directly promotes tumour cell proliferation in vivo, yet in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high proclivity to metastasize does not occur continuously, but it is concentrated within the rest phase of the affected individual, providing a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.

DOI: https://doi.org/10.1038/s41586-022-04875-y
Trends Cancer. 2022 Jun 15. pii: S2405-8033(22)00131-5. [Epub ahead of print]

Lymph node metastasis fuels systemic disease.

Katherine S Ventre, Triantafyllia Karakousi, Amanda W Lund.

  The functional impact of lymph node (LN) metastasis on systemic tumor progression has been a controversial question for decades. In their recent paper published in Cell, Reticker-Flynn et al. demonstrate that sequential evasion of natural killer (NK) cell control and interferon (IFN)-dependent epigenetic adaptation enhances the probability of LN metastasis. Further, they show that, once formed, LN metastases expand systemic peripheral tolerance and promote distant organ metastasis.

Keywords:  NK cells; interferons; lymph node metastasis; systemic tolerance

DOI:  https://doi.org/10.1016/j.trecan.2022.06.003
Oncogene. 2022 Jun 22.

Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer.

Johanna M Buschhaus, Shrila Rajendran, Brock A Humphries, Alyssa C Cutter, Ayşe J Muñiz, Nicholas G Ciavattone, Alexander M Buschhaus, Tatiana Cañeque, Zeribe C Nwosu, Debashis Sahoo, Avinash S Bevoor, Yatrik M Shah, Costas A Lyssiotis, Pradipta Ghosh, Max S Wicha, Raphaël Rodriguez, Gary D Luker.

Patients with estrogen receptor-positive (ER+) breast cancer, the most common subtype, remain at risk for lethal metastatic disease years after diagnosis. Recurrence arises partly because tumor cells in bone marrow become resistant to estrogen-targeted therapy. Here, we utilized a co-culture model of bone marrow mesenchymal stem cells (MSCs) and ER+ breast cancer cells to recapitulate interactions of cancer cells in bone marrow niches. ER+ breast cancer cells in direct contact with MSCs acquire cancer stem-like (CSC) phenotypes with increased resistance to standard antiestrogenic drugs. We confirmed that co-culture with MSCs increased labile iron in breast cancer cells, a phenotype associated with CSCs and disease progression. Clinically approved iron chelators and in-house lysosomal iron-targeting compounds restored sensitivity to antiestrogenic therapy. These findings establish iron modulation as a mechanism to reverse MSC-induced drug resistance and suggest iron modulation in combination with estrogen-targeted therapy as a promising, translatable strategy to treat ER+ breast cancer.

DOI: https://doi.org/10.1038/s41388-022-02385-9
Cancer Discov. 2022 Jun 24. OF1

Resistance to BRAF/MEK Inhibition in Melanoma Is Mediated by the Androgen Receptor.

Androgen receptor (AR) expression increases upon BRAF/MEK inhibitor treatment, promoting resistance.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-114
Cancer Res. 2022 Jun 23. pii: canres.CAN-21-3106-E.2021-9-13 12:18:38.287. [Epub ahead of print]

Poziotinib inhibits HER2 mutant-driven therapeutic resistance and multi-organ metastasis in breast cancer.

Rashi Kalra, Ching Hui Chen, Junkai Wang, Ahmad Bin Salam, Lacey E Dobrolecki, Alaina Lewis, Christina Sallas, Clayton C Yates, Carolina Gutierrez, Balasubramanyam Karanam, Meenakshi Anurag, Bora Lim, Matthew J Ellis, Shyam M Kavuri.

The pan-HER tyrosine kinase inhibitor (TKI) neratinib is therapeutically active against metastatic breast cancers harboring activating HER2 mutations, but responses are variable and often not durable. Here we demonstrate that recurrent HER2 mutations have differential effects on endocrine therapy responsiveness, metastasis, and pan-HER TKI therapeutic sensitivity. The prevalence and prognostic significance may also depend on whether the HER2 mutant has arisen in the context of lobular versus ductal histology. The most highly recurrent HER2 mutant, L755S, was particularly resistant to neratinib but sensitive to the pan-HER TKI poziotinib, alone or in combination with fulvestrant. Poziotinib reduced tumor growth, diminished multi-organ metastasis, and inhibited mTOR activation more effectively than neratinib. Similar therapeutic effects of poziotinib were observed in both an engineered HER2L755S MCF7 model and a patient-derived xenograft harboring a HER2G778_P780dup mutation. Overall, these findings support the need for clinical evaluation of poziotinib for the treatment of HER2 mutant metastatic breast cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3106
Cell Rep. 2022 Jun 21. pii: S2211-1247(22)00777-X. [Epub ahead of print]39(12): 110991

Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma.

Rajappa S Kenchappa, Athanassios Dovas, Michael G Argenziano, Christian T Meyer, Lauren E Stopfer, Matei A Banu, Brianna Pereira, Jessica Griffith, Afroz Mohammad, Surabhi Talele, Ashley Haddock, Natanael Zarco, William Elmquist, Forest White, Vito Quaranta, Peter Sims, Peter Canoll, Steven S Rosenfeld.

  Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and epidermal growth factor receptor (EGFR), respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.

Keywords:  CP: Cancer; EGFR; STAT3; Src; glioblastoma; inhibitor; kinesin

DOI:  https://doi.org/10.1016/j.celrep.2022.110991
Clin Cancer Res. 2022 Jun 23. OF1-OF14

OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma.

Zhenhua Xu, Najiba Murad, Daniel Malawsky, Ran Tao, Samuel Rivero-Hinojosa, Dörthe Holdhof, Ulrich Schüller, Peng Zhang, Christopher Lazarski, Brian R Rood, Roger Packer, Timothy Gershon, Yanxin Pei.

PURPOSE: Patients with MYC-amplified medulloblastoma (MB) have poor prognosis and frequently develop recurrence, thus new therapeutic approaches to prevent recurrence are needed.EXPERIMENTAL DESIGN: We evaluated OLIG2 expression in a panel of mouse Myc-driven MB tumors, patient MB samples, and patient-derived xenograft (PDX) tumors and analyzed radiation sensitivity in OLIG2-high and OLIG2-low tumors in PDX lines. We assessed the effect of inhibition of OLIG2 by OLIG2-CRISPR or the small molecule inhibitor CT-179 combined with radiotherapy on tumor progression in PDX models.
RESULTS: We found that MYC-associated MB can be stratified into OLIG2-high and OLIG2-low tumors based on OLIG2 protein expression. In MYC-amplified MB PDX models, OLIG2-low tumors were sensitive to radiation and rarely relapsed, whereas OLIG2-high tumors were resistant to radiation and consistently developed recurrence. In OLIG2-high tumors, irradiation eliminated the bulk of tumor cells; however, a small number of tumor cells comprising OLIG2- tumor cells and rare OLIG2+ tumor cells remained in the cerebellar tumor bed when examined immediately post-irradiation. All animals harboring residual-resistant tumor cells developed relapse. The relapsed tumors mirrored the cellular composition of the primary tumors with enriched OLIG2 expression. Further studies demonstrated that OLIG2 was essential for recurrence, as OLIG2 disruption with CRISPR-mediated deletion or with the small molecule inhibitor CT-179 prevented recurrence from the residual radioresistant tumor cells.
CONCLUSIONS: Our studies reveal that OLIG2 is a biomarker and an effective therapeutic target in a high-risk subset of MYC-amplified MB, and OLIG2 inhibitor combined with radiotherapy represents a novel effective approach for treating this devastating disease.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-0527
Mol Cancer. 2022 Jun 23. 21(1): 135

circEXOC6B interacting with RRAGB, an mTORC1 activator, inhibits the progression of colorectal cancer by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop.

Xiaomin Li, Jianjun Wang, Weihao Lin, Qinzi Yuan, Yanxia Lu, Haowei Wang, Yujia Chen, Lixia Chen, Peiling Dai, Huaicheng Long, Xuenong Li.

  BACKGROUND: In recent years, an increasing number of studies have indicated that circular RNA plays crucial roles in regulating tumor development and chemoresistance. Using two high-throughput RNA sequence datasets, we previously found that circEXOC6B was downregulated in colon cancer. However, its role and mechanism in colorectal cancer (CRC) remained unknown.METHODS: Real-time quantitative PCR was used to examine the expression of circEXOC6B in CRC tissues. In vivo and in vitro functional experiments were performed to determine the suppressor role of circEXOC6B in CRC progression. RNA pull-down, mass spectrometry, RNA-binding protein immunoprecipitation, co-immunoprecipitation, fluorescence in situ hybridization, and immunofluorescence were applied to investigate the possible mechanisms connecting circEXOC6B to CRC growth and 5-fluorouracil-induced apoptosis. Chromatin immunoprecipitation, dual-luciferase assay, western blot, and immunohistochemistry were used to explore the mechanisms underlying the HIF1A regulation of RRAGB transcription.
RESULTS: circEXOC6B was downregulated in CRC tissues, and its lower expression was associated with poor prognosis of patients. Functional experiments showed that circEXOC6B inhibited growth and increased the 5-fluorouracil-induced apoptosis of CRC cells in vitro and in vivo. Mechanistically, circEXOC6B inhibited the heterodimer formation of RRAGB by binding to it, thereby suppressing the mTORC1 pathway and HIF1A level. In addition, HIF1A upregulated the transcription of RRAGB by binding to its promoter region. Altogether, the results demonstrated that a HIF1A-RRAGB-mTORC1 positive feedback loop drives tumor progression in CRC, which could be interrupted by circEXOC6B.
CONCLUSIONS: circEXOC6B inhibits the progression of CRC and enhances the chemosensitivity of CRC cells to 5-fluorouracil by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop. circEXOC6B is a possible therapeutic target for CRC treatment.

Keywords:  Circular RNA; Colorectal cancer; RRAGB; circEXOC6B; hsa_circ_0009043

DOI:  https://doi.org/10.1186/s12943-022-01600-1
Cancer Discov. 2022 Jun 24. OF1

IL6 Signaling Enables Survival of Chromosomally Instable Cancer Cells.

The cGAS-STING axis drives IL6 signaling to enable survival despite chromosomal instability (CIN).

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-116
Cancer Res. 2022 Jun 24. pii: canres.4141.2021. [Epub ahead of print]

Cancer-associated fibroblasts suppress CD8+ T cell infiltration and confer resistance to immune checkpoint blockade.

Liam Jenkins, Ute Jungwirth, Alexandra Avgustinova, Marjan Iravani, Adam P Mills, Syed Haider, James Harper, Clare M Isacke.

Immune checkpoint blockade (ICB) promotes anti-tumor immune responses and can result in durable patient benefit. However, response rates in breast cancer patients remain modest, stimulating efforts to discover novel treatment options. Cancer-associated fibroblasts (CAF) represent a major component of the breast tumor microenvironment and have known immunosuppressive functions in addition to their well-established roles in directly promoting tumor growth and metastasis. Here we utilized paired syngeneic mouse mammary carcinoma models to show that CAF abundance is associated with insensitivity to combination αCTLA-4 and αPD-L1 ICB. CAF-rich tumors exhibited an immunologically cold tumor microenvironment, with transcriptomic, flow cytometric, and quantitative histopathological analyses demonstrating a relationship between CAF density and a CD8+ T cell-excluded tumor phenotype. The CAF receptor Endo180 (Mrc2) is predominantly expressed on myofibroblastic CAFs, and its genetic deletion depleted a subset of αSMA-expressing CAFs and impaired tumor progression in vivo. Addition of wild-type, but not Endo180-deficient, CAFs in co-implantation studies restricted CD8+ T cell intratumoral infiltration, and tumors in Endo180 knockout mice exhibited increased CD8+ T cell infiltration and enhanced sensitivity to ICB compared to tumors in wild-type mice. Clinically, in a trial of melanoma patients, high MRC2 mRNA levels in tumors was associated with a poor response to αPD-1 therapy, highlighting the potential benefits of therapeutically targeting a specific CAF subpopulation in breast and other CAF-rich cancers to improve clinical responses to immunotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-4141
Cell Rep. 2022 Jun 21. pii: S2211-1247(22)00788-4. [Epub ahead of print]39(12): 110999

Endothelial p130cas confers resistance to anti-angiogenesis therapy.

Yunfei Wen, Anca Chelariu-Raicu, Sujanitha Umamaheswaran, Alpa M Nick, Elaine Stur, Pahul Hanjra, Dahai Jiang, Nicholas B Jennings, Xiuhui Chen, Sara Corvigno, Deanna Glassman, Gabriel Lopez-Berestein, Jinsong Liu, Mien-Chie Hung, Anil K Sood.

DOI: https://doi.org/10.1016/j.celrep.2022.110999
Oncogene. 2022 Jun 23.

HAO1-mediated oxalate metabolism promotes lung pre-metastatic niche formation by inducing neutrophil extracellular traps.

Zhicheng Zeng, Shaowan Xu, Feifei Wang, Xin Peng, Wanning Zhang, Yizhi Zhan, Yanqing Ding, Ziguang Liu, Li Liang.

Metabolic reprogramming has been shown to be involved in cancer-induced pre-metastatic niche (PMN) formation, but the underlying mechanisms have been insufficiently explored. Here, we showed that hydroxyacid oxidase 1 (HAO1), a rate-limiting enzyme of oxalate synthesis, was upregulated in the alveolar epithelial cells of mice bearing metastatic breast cancer cells at the pre-metastatic stage, leading to oxalate accumulation in lung tissue. Lung oxalate accumulation induced neutrophil extracellular trap (NET) formation by activating NADPH oxidase, which facilitated the formation of pre-metastatic niche. In addition, lung oxalate accumulation promoted the proliferation of metastatic cancer cells by activating the MAPK signaling pathway. Pharmacologic inhibition of HAO1 could effectively suppress the lung oxalate accumulation induced by primary cancer, consequently dampening lung metastasis of breast cancer. Breast cancer cells induced HAO1 expression and oxalate accumulation in alveolar epithelial cells by activating TLR3-IRF3 signaling. Collectively, these findings underscore the role of HAO1-mediated oxalate metabolism in cancer-induced lung PMN formation and metastasis. HAO1 could be an appealing therapeutic target for preventing lung metastasis of cancer.

DOI: https://doi.org/10.1038/s41388-022-02248-3
Nature. 2022 Jun 22.

Cancer cells spread aggressively during sleep.

Harrison Ball, Sunitha Nagrath.



Keywords:  Cancer; Medical research

DOI:  https://doi.org/10.1038/d41586-022-01639-6
Cell Rep. 2022 Jun 21. pii: S2211-1247(22)00779-3. [Epub ahead of print]39(12): 110993

KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy.

Meagan B Ryan, Oluwadara Coker, Alexey Sorokin, Katerina Fella, Haley Barnes, Edmond Wong, Preeti Kanikarla, Fengqin Gao, Youyan Zhang, Lian Zhou, Scott Kopetz, Ryan B Corcoran.

  Although KRAS has long been considered undruggable, direct KRASG12C inhibitors have shown promising initial clinical efficacy. However, the majority of patients still fail to respond. Adaptive feedback reactivation of RAS-mitogen-activated protein kinase (MAPK) signaling has been proposed by our group and others as a key mediator of resistance, but the exact mechanism driving reactivation and the therapeutic implications are unclear. We find that upstream feedback activation of wild-type RAS, as opposed to a shift in KRASG12C to its active guanosine triphosphate (GTP)-bound state, is sufficient to drive RAS-MAPK reactivation in a KRASG12C-independent manner. Moreover, multiple receptor tyrosine kinases (RTKs) can drive feedback reactivation, potentially necessitating targeting of convergent signaling nodes for more universal efficacy. Even in colorectal cancer, where feedback is thought to be primarily epidermal growth factor receptor (EGFR)-mediated, alternative RTKs drive pathway reactivation and limit efficacy, but convergent upstream or downstream signal blockade can enhance activity. Overall, these data provide important mechanistic insight to guide therapeutic strategies targeting KRAS.

Keywords:  CP: Cancer; KRAS; KRASG12C; adagrasib; adaptive resistance; sotorasib

DOI:  https://doi.org/10.1016/j.celrep.2022.110993
J Immunother Cancer. 2022 Jun;pii: e004133. [Epub ahead of print]10(6):

BCG hydrogel promotes CTSS-mediated antigen processing and presentation, thereby suppressing metastasis and prolonging survival in melanoma.

Mirela Kremenovic, Alfred A Chan, Bing Feng, Lukas Bäriswyl, Steve Robatel, Thomas Gruber, Li Tang, Delphine J Lee, Mirjam Schenk.

  BACKGROUND: The use of intralesional Mycobacterium bovis BCG (intralesional live BCG) for the treatment of metastatic melanoma resulted in regression of directly injected, and occasionally of distal lesions. However, intralesional-BCG is less effective in patients with visceral metastases and did not significantly improve overall survival.METHODS: We generated a novel BCG lysate and developed it into a thermosensitive PLGA-PEG-PLGA hydrogel (BCG hydrogel), which was injected adjacent to the tumor to assess its antitumor effect in syngeneic tumor models (B16F10, MC38). The effect of BCG hydrogel treatment on contralateral tumors, lung metastases, and survival was assessed to evaluate systemic long-term efficacy. Gene expression profiles of tumor-infiltrating immune cells and of tumor-draining lymph nodes from BCG hydrogel-treated mice were analyzed by single-cell RNA sequencing (scRNA-seq) and CD8+ T cell receptor (TCR) repertoire diversity was assessed by TCR-sequencing. To confirm the mechanistic findings, RNA-seq data of biopsies obtained from in-transit cutaneous metastases of patients with melanoma who had received intralesional-BCG therapy were analyzed.
RESULTS: Here, we show that BCG lysate exhibits enhanced antitumor efficacy compared to live mycobacteria and promotes a proinflammatory tumor microenvironment and M1 macrophage (MΦ) polarization in vivo. The underlying mechanisms of BCG lysate-mediated tumor immunity are dependent on MΦ and dendritic cells (DCs). BCG hydrogel treatment induced systemic immunity in melanoma-bearing mice with suppression of lung metastases and improved survival. Furthermore, BCG hydrogel promoted cathepsin S (CTSS) activity in MΦ and DCs, resulting in enhanced antigen processing and presentation of tumor-associated antigens. Finally, BCG hydrogel treatment was associated with increased frequencies of melanoma-reactive CD8+ T cells. In human patients with melanoma, intralesional-BCG treatment was associated with enhanced M1 MΦ, mature DC, antigen processing and presentation, as well as with increased CTSS expression which positively correlated with patient survival.
CONCLUSIONS: These findings provide mechanistic insights as well as rationale for the clinical translation of BCG hydrogel as cancer immunotherapy to overcome the current limitations of immunotherapies for the treatment of patients with melanoma.

Keywords:  antigen presentation; dendritic cells; immunotherapy; macrophages; melanoma

DOI:  https://doi.org/10.1136/jitc-2021-004133
Cancer Res. 2022 Jun 22. pii: canres.0717.2022. [Epub ahead of print]

DLGAP1-AS2-Mediated Phosphatidic Acid Synthesis Activates YAP Signaling and Confers Chemoresistance in Squamous Cell Carcinoma.

Zhihua Liu, Yabing Nan, Qingyu Luo, Xiaowei Wu, Shi Liu, Pengfei Zhao, Wan Chang, Aiping Zhou.

Squamous cell carcinomas (SCC) constitute a group of human malignancies that originate from the squamous epithelium. Most SCC patients experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and explore novel targets for chemosensitization, we performed whole-transcriptome sequencing of paired resistant and parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 affected chromatin accessibility around the histone mark H3K27ac of FAM3 metabolism regulating signaling molecule D (FAM3D), reducing FAM3D mRNA transcription and extracellular protein secretion. FAM3D interacted with the Gαi-coupled G protein-coupled receptors (GPCRs) formyl peptide receptor 1 (FPR1) and FPR2 to suppress phospholipase D (PLD) activity, and reduced FAM3D increased PLD signaling. Moreover, activated PLD promoted phosphatidic acid (PA) production and subsequent nuclear translocation of yes-associated protein (YAP). Accordingly, in vivo administration of a D-AS2-targeting antisense oligonucleotide sensitized SCC to cisplatin treatment. In summary, this study shows that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential for SCC chemoresistance, suggesting D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0717
Sci Adv. 2022 Jun 24. 8(25): eabn3471

Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas.

Deanna M Tiek, Beril Erdogdu, Roham Razaghi, Lu Jin, Norah Sadowski, Carla Alamillo-Ferrer, J Robert Hogg, Bassem R Haddad, David H Drewry, Carrow I Wells, Julie E Pickett, Xiao Song, Anshika Goenka, Bo Hu, Samuel A Goldlust, William J Zuercher, Mihaela Pertea, Winston Timp, Shi-Yuan Cheng, Rebecca B Riggins.

Temozolomide (TMZ) is a chemotherapeutic agent that has been the first-line standard of care for the aggressive brain cancer glioblastoma (GBM) since 2005. Although initially beneficial, TMZ resistance is universal and second-line interventions are an unmet clinical need. Here, we took advantage of the known mechanism of action of TMZ to target guanines (G) and investigated G-rich G-quadruplex (G4) and splice site changes that occur upon TMZ resistance. We report that TMZ-resistant GBM has guanine mutations that disrupt the G-rich DNA G4s and splice sites that lead to deregulated alternative splicing. These alterations create vulnerabilities, which are selectively targeted by either the G4-stabilizing drug TMPyP4 or a novel splicing kinase inhibitor of cdc2-like kinase. Last, we show that the G4 and RNA binding protein EWSR1 aggregates in the cytoplasm in TMZ-resistant GBM cells and patient samples. Together, our findings provide insight into targetable vulnerabilities of TMZ-resistant GBM and present cytoplasmic EWSR1 as a putative biomarker.

DOI: https://doi.org/10.1126/sciadv.abn3471