Dynamic Interplay between Intratumoral Immune Cells
Immune cell populations can be both pro- and antitumorigenic, with distinct immune profiles linked to prognosis and response to therapy. Kim and colleagues identified specific neutrophil-enriched and macrophage-enriched triple-negative breast cancer subtypes driven by tumor intrinsic factors, which can lead to spatial segregation of distinct immune subtypes within the same tumor. Importantly, these immune subtypes dictate response to immune checkpoint blockade, with tumors rich in neutrophils being resistant to immunotherapy. However, the immune microenvironment evolves upon treatment and manipulation of one immune cell population may not be sufficient to alter the immunosuppressive tumor microenvironment.
Expert Commentary: Understanding the interplay between different immune cell populations within tumors will help in tailoring immunotherapy strategies in different patients.
A Subset of p53 Mutations May Be a Tumor's Achilles' Heel
TP53 mutations occur in almost half of all malignancies. Timofeev and colleagues used multiple transgenic mouse tumor models and human cancer cell lines to reveal a previously unrealized vulnerability of a subset of p53 mutant tumors to cytotoxic therapy. They demonstrated that p53 mutations that disrupt the cooperative ability of p53 DNA binding lose transcriptional activity and promote tumorigenesis similar to p53 deletion. Remarkably, these mutants retained residual apoptotic activity during development and more importantly in response to cytotoxic therapy in vivo, which was enhanced by MDM2 inhibition.
Expert Commentary: This study suggests that a subset of p53 mutations may predict for improved efficacy of cytotoxic therapy and MDM2 inhibitors.
OLIG2 and Medulloblastoma
The identity of the medulloblastoma progenitor cells, which cause initiation and relapse, has been unknown. Zhang and colleagues revealed a developmental hierarchy of progenitor pools by using single-cell transcriptomics of Sonic Hedgehog medulloblastoma. The authors showed that glial lineage progenitors expressing OLIG2 were rapidly propagating during the initial phase of tumorigenesis. These cells then became quiescent stem-like progenitors, which were enriched in therapy-resistant and recurrent tumors. Upon deletion of OLIG2-expressing cells, medulloblastoma initiation and growth was inhibited. OLIG2 expression in turn activated the HIPPO-YAP/TAZ and AURORA-A/MYCN pathways and inhibition of these signaling cascades reduced tumor growth. Importantly, high OLIG2 expression levels predicted poor outcome for SHH-medulloblastoma patients.
Expert Commentary: This study identifies OLIG2-expressing glial progenitor cells as tumor initiating and cancer stem cells during medulloblastoma tumorigenesis, suggesting pathways downstream of OLIG2 as attractive therapeutic targets.
Metabolism Meets Metastasis
UDP-glucose 6-dehydrogenase (UGDH) converts UDP-glucose (UDP-Glc) to UDP-glucuronic acid in the cytoplasm. UGDH was identified by Wang and colleagues in an siRNA screen for metastasis modulators in non-small-cell lung carcinoma cells. Depletion of UGDH led to decreased levels of SNAIL, a master regulator of epithelial-mesenchymal transition (EMT), with consequent inhibition of cell migration. Activated EGFR signaling led to phosphorylation of UGDH at Y473. Phosphorylated UGDH interacted with RNA binding protein HuR in the nucleus, potentiating binding to the 3′-UTR of SNAIL to increase its stability. In the absence of the enzyme, UDP-Glc inhibited association of HuR with SNAIL mRNA, preventing EMT. Expression of UGDH mRNA was higher in tumor tissues than normal tissues and correlated with patient outcome. Moreover, pUGDHY473 expression in primary tumors was associated with metastatic recurrence and poor prognosis in patients with lung cancer.
Expert Commentary: This study identifies a novel mechanism by which metabolites and related enzymes regulate lung cancer metastasis, with implications for therapies that inhibit these enzymes.
Targeting Neutrophil Infiltration in Metastases
Poor survival rates in colorectal cancer are associated with metastatic spread, although the drivers of metastasis remain unknown. Jackstadt and colleagues showed that activation of NOTCH signaling in mutant Kras tumors drives intestinal metastasis in an autochthonous mouse model. NOTCH1 in the tumor rewires the tumor microenvironment through control of CXCL5 and TGFβ2 expression, which recruits neutrophils to generate an immunosuppressive, prometastatic environment. The tumors resemble a specific subtype of human colorectal cancer with the poorest prognosis, characterized by activation of NOTCH1 signaling.
Expert Commentary: This study demonstrates that targeting neutrophil recruitment and TGFβ signaling with clinically relevant therapeutics has a significant impact on metastatic burden that may be relevant in a specific subtype of colorectal cancer.
Combination Therapies to Target KRASG12C-Mutant NSCLC
Previous attempts to inhibit the downstream pathways of KRAS have failed in the clinic due to toxicity and lack of efficacy. Molina-Arcas and colleagues performed an shRNA drug screen to identify targets that enhance the efficacy of dual MEK and IGF1R inhibition in KRAS mutant NSCLC. Inhibition of mTOR significantly improved efficacy in vitro and in vivo in a KRAS mutant-specific manner. Furthermore, the combination of an IGF1R, mTOR, and KRAS-G12C inhibitor significantly improved the frequency and durability of response, with decreased toxicity compared with MEK inhibitor combinations.
Expert Commentary: This study provides the preclinical rationale for a novel KRAS mutant inhibitor combination to prevent or overcome resistance to KRAS inhibitor therapy.
Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.
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